vol.

 4  q 4  2016

THE GENTLE ART OF SAYING NO: HOW TO ESTABLISH APPROPRIATE BOUNDARIES

WITH PAIN PATIENTS  P.18 THE ROLE OF SPECIAL K IN PAIN MANAGEMENT  P. 26
THE ROLE OF THE ADVANCED PRACTICE PROVIDER IN THE ACUTE CARE SETTING  P.3 6 STATE
OF THE ART: PROLOTHERAPY REGENERATIVE MEDICINE  P.44
 TW O
SOURCES
OF PAIN
O NE
SOURCE
OF RELIEF
NUCYNTA® ER is the first and only FDA-approved
long-acting opioid designed to control both
nociceptive pain and the neuropathic pain associated
with diabetic peripheral neuropathy (DPN).
NUCYNTA® ER is an opioid agonist indicated for
the management of:
• pain severe enough to require daily, around-the-
clock, long-term opioid treatment and for which
alternative treatment options are inadequate
• neuropathic pain associated with DPN in adults
severe enough to require daily, around-the-clock,
long-term opioid treatment and for which
alternative treatment options are inadequate

Not an actual patient.

Limitations of Use
• Because of the risks of addiction, abuse, and
misuse with opioids, even at recommended doses,
and because of the greater risks of overdose and
death with extended-release opioid formulations,
reserve NUCYNTA® ER for use in patients for
whom alternative treatment options (e.g., non-
opioid analgesics or immediate-release opioids)
are ineffective, not tolerated, or would be
otherwise inadequate to provide sufficient
management of pain
• NUCYNTA® ER is not indicated as an as-needed
(prn) analgesic

Please see additional Important

Safety Information, including
BOXED WARNING, and Brief
Summary on the following pages.

TIME TO DUAL
PRESCRIBE NUCYNTA® ER FOR ONE SOURCE OF RELIEF
• Proven efficacy in chronic low back pain and DPN1,2
- Based on efficacy demonstrated in a prospective, randomized, double-blind, active- and COVERED FOR
placebo-controlled, multicenter phase 3 chronic low back pain study (N=981) showing
significant change in mean pain intensity from baseline in Week 15 (Week 12 of the
maintenance phase) vs placebo1
94%
OF COMMERCIALLY
- Based on efficacy demonstrated in a double-blind, parallel-group, enriched-enrollment INSURED PATIENTS.‡
randomized withdrawal phase 3 DPN study (N=977) showing significant change in mean pain PREFERRED FOR
intensity over the last week of the 12-week, double-blind, maintenance phase vs placebo2 UNITEDHEALTH
• 5 dosage strengths: 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg3* GROUP AND
Individualize dosing based on patient’s prior analgesic treatment experience and risk SILVERSCRIPT/
factors for addiction, abuse, and misuse; titrate as needed to provide adequate analgesia CVS CAREMARK
and minimize adverse reactions PART D PLANS‡
• Administer NUCYNTA® ER ~q12h3
VISIT NUCYNTA.COM FOR MORE INFORMATION AND TO DOWNLOAD
A NUCYNTA® ER SAVINGS CARD†
• $0 co-pay for first prescription of NUCYNTA® ER with a $25 co-pay on each additional
prescription if eligible†

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY

DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and
INTERACTION WITH ALCOHOL
See full prescribing information for complete boxed warning.
• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to
overdose and death. Assess each patient’s risk before prescribing, and monitor regularly
for development of these behaviors or conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely,
especially upon initiation or following a dose increase. Instruct patients to swallow
NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2)
• Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose
of tapentadol. (5.2)
• Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal
syndrome, which may be life-threatening if not recognized and treated. If opioid use is
required for a prolonged period in a pregnant woman, advise the patient of the risk
of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will
be available. (5.3)
• Instruct patients not to consume alcohol or any products containing alcohol while taking
NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4)

CONTRAINDICATIONS: Significant respiratory depression; acute or severe bronchial asthma

or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment;
known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to
tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase
inhibitors (MAOIs) or use within the last 14 days.
*Please see full Prescribing Information for DOSAGE AND ADMINISTRATION.
†Some restrictions and limitations apply. See full terms and conditions available at NUCYNTA.com. Available to commercially insured and cash-paying
patients only. Patients covered by Medicare, Medicaid, or any other federally funded benefit program are excluded. Patients must be 18 years of age or
older. This promotion cannot be combined with any other programs, offers, or discounts. Depomed reserves the right to rescind, revoke, or amend this
offer without further notice.
‡Data on file. Depomed, Inc. formulary data are sourced from MMIT. Transaction data are sourced from SHA Health. Data are current as of July, 2015.

References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back
pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase Ill study. Expert Opin Pharmocother. 2010;11(11):1787-
1804. 2. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results
of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162. 3. NUCYNTA® ER [package insert]. Titusville, NJ: Janssen
Pharmaceuticals, Inc; 2014.
NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued)
WARNINGS AND PRECAUTIONS: Addiction,
Abuse, and Misuse: NUCYNTA® ER contains
tapentadol, an opioid agonist and a Schedule II
controlled substance that can be abused in a
manner similar to other opioid agonists, legal
or illicit. There is a greater risk for overdose and
death due to the larger amount of tapentadol
present in NUCYNTA® ER. Assess risk for
opioid abuse or addiction prior to prescribing
NUCYNTA® ER. Addiction can occur in patients
appropriately prescribed NUCYNTA® ER at
recommended doses; in those who obtain the
drug illicitly; and if the drug is misused or abused.
Therefore, routinely monitor for signs of misuse,
abuse, and addiction. Patients at increased risk
(e.g., patients with a personal or family history
of substance abuse or mental illness) may be
prescribed NUCYNTA® ER, but use in such patients
necessitates intensive counseling about the risks
and proper use along with intensive monitoring for
signs of addiction, abuse, and misuse.
Life-threatening Respiratory Depression:
Can occur at any time during the use of
NUCYNTA® ER even when used as recommended.
Respiratory depression from opioid use, if not
immediately recognized and treated, may lead
to respiratory arrest and death. To reduce the
risk of respiratory depression, proper dosing and
titration are essential. Overestimating the dose
when converting patients from another opioid
product can result in fatal overdose with the first
dose. Management of respiratory depression may
include close observation, supportive measures,
and use of opioid antagonists, depending on the
patient’s clinical status.
Neonatal Opioid Withdrawal Syndrome:
Prolonged use of NUCYNTA® ER during pregnancy
can result in withdrawal signs in the neonate,
which may be life-threatening and require
management according to protocols developed by
neonatology experts. Neonatal opioid withdrawal
syndrome presents as poor feeding, irritability,
hyperactivity and abnormal sleep pattern,
high-pitched cry, tremor, rigidity, seizures,
vomiting, diarrhea, and failure to gain weight.
Interactions With Central Nervous System
Depressants: Hypotension, profound sedation,
coma, respiratory depression, and death may
result if NUCYNTA® ER is used concomitantly
with alcohol or other central nervous system
(CNS) depressants (e.g., sedatives, anxiolytics,
hypnotics, tranquilizers, general anesthetics,
neuroleptics, other opioids). When considering the
use of NUCYNTA® ER in a patient taking a CNS
depressant, assess the duration of use of the CNS
depressant and the patient’s response, including
the degree of tolerance that has developed to CNS
depression. If the decision to begin NUCYNTA® ER
is made, start with NUCYNTA® ER 50 mg every
12 hours, monitor patients for signs of sedation
and respiratory depression, and consider using a
lower dose of the concomitant CNS depressant.
Use in Elderly, Cachectic, or Debilitated Patients:
Life-threatening respiratory depression is more likely
to occur in elderly, cachectic, or debilitated patients
as they may have altered pharmacokinetics or
altered clearance. Because elderly patients are more
likely to have decreased renal and hepatic function,
consideration should be given to starting elderly
patients in the lower range of recommended doses.
Closely monitor these patients, particularly when
initiating and titrating NUCYNTA® ER and when
given concomitantly with other drugs that
depress respiration.
Use in Patients With Chronic Pulmonary Disease:
Patients with significant chronic obstructive
pulmonary disease or cor pulmonale and patients
having a substantially decreased respiratory reserve,
hypoxia, hypercarbia, or pre-existing respiratory
depression, should be monitored for respiratory
depression particularly when initiating therapy and
titrating with NUCYNTA® ER. Consider the use of
alternative nonopioid analgesics in these patients.
Hypotensive Effect: May cause severe
hypotension. There is an increased risk in patients
whose ability to maintain blood pressure has
already been compromised by a reduced blood
volume or concurrent administration of certain
CNS depressant drugs (e.g., phenothiazines
or general anesthetics). Monitor for signs of
hypotension during dose initiation or titration.
Avoid use in patients with circulatory shock; may
cause vasodilation that can further reduce cardiac
output and blood pressure.
Use in Patients With Head Injury or Increased
Intracranial Pressure: Monitor patients who may
be susceptible to the intracranial effects of CO2
retention (e.g., those with evidence of increased
intracranial pressure or brain tumors) for signs of
sedation and respiratory depression, particularly
when initiating therapy. NUCYNTA® ER may
reduce respiratory drive, and the resultant CO2
retention can further increase intracranial pressure.
Opioids may also obscure the clinical course in a
patient with a head injury.
Seizures: May aggravate convulsions in patients
with convulsive disorders and may induce or
aggravate seizures. Monitor patients with a history
of seizure disorders for worsened seizure control
during therapy.
Serotonin Syndrome: Cases of life-threatening
serotonin syndrome have been reported with the
concurrent use of NUCYNTA® ER and serotonergic
drugs. Serotonergic drugs comprise selective
serotonin reuptake inhibitors (SSRIs), serotonin
and norepinephrine reuptake inhibitors (SNRIs),
tricyclic antidepressants (TCAs), triptans, drugs
that affect the serotonergic neurotransmitter
system, and drugs that impair metabolism of
serotonin (including MAOIs). This may occur within
the recommended dose. Serotonin syndrome may
include mental-status changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g.,
tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia,
incoordination), and/or gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea) and can be fatal. If
concomitant treatment with SSRIs, SNRIs, TCAs, or
triptans is clinically warranted, careful observation
of the patient is advised, particularly when
initiating or titrating the dose.
Use in Patients With Gastrointestinal (GI)
Conditions: Contraindicated in patients with
Gl obstruction including paralytic ileus; may
cause spasm of the sphincter of Oddi. Monitor
patients with biliary tract disease, including acute
pancreatitis, for worsening symptoms.
Avoidance of Withdrawal: Withdrawal symptoms
(e.g., anxiety, sweating, insomnia, restlessness,
pain, nausea, tremors, diarrhea, upper respiratory
symptoms, piloerection) may occur:
• After abrupt discontinuation or a significant
dose reduction of NUCYNTA® ER in physically
dependent patients. When discontinuing
NUCYNTA® ER, gradually taper the dose.
• If mixed agonist/antagonist (e.g., butorphanol,
nalbuphine, pentazocine) and partial agonist
(e.g., buprenorphine) analgesics are used in
patients who have received or are receiving
NUCYNTA® ER. Avoid use with mixed agonists/
antagonists and partial agonists.
• If opioid antagonists (e.g., naloxone, nalmefene)
are administered in physically dependent
patients. Administration of the antagonist should
be begun with care and by titration with smaller
than usual doses of the antagonist.
Driving and Operating Heavy Machinery: May
impair the mental or physical abilities needed
to perform potentially hazardous activities such
as driving a car or operating machinery. Warn
patients not to drive or operate dangerous
machinery unless they are tolerant to the effects
of NUCYNTA® ER and know how they will react to
the medication.
Hepatic Impairment: Avoid use in patients with
severe hepatic impairment (Child-Pugh Score 10 to
15). In patients with moderate hepatic impairment
(Child-Pugh Score 7-9), initiate treatment with
NUCYNTA® ER 50 mg no more than once every
24 hours, with a maximum dose of 100 mg per day.
Monitor for respiratory and CNS depression when
initiating and titrating NUCYNTA® ER.
Renal Impairment: Use in patients with severe renal
impairment (CLCR <30 mL/min) is not recommended
due to accumulation of a metabolite formed by
glucuronidation of tapentadol. The clinical relevance
of the elevated metabolite is not known.
Please see additional Important Safety Information, including
BOXED WARNING, and Brief Summary on the following pages.
© June 2016, Depomed, Inc.
All rights reserved. APL-NUCX-0029 Rev. 2
DRUG INTERACTIONS
Alcohol: See BOXED WARNING.
Muscle Relaxants: Monitor patients receiving
muscle relaxants and NUCYNTA® ER for signs of
respiratory depression that may be greater than
otherwise expected. Tapentadol may enhance the
neuromuscular blocking action of skeletal muscle
relaxants and produce an increased degree of
respiratory depression.
Anticholinergics: Use with anticholinergic
products may increase the risk of urinary retention
and/or severe constipation, which may lead to
paralytic ileus.
USE IN SPECIFIC POPULATIONS
Pregnancy/Nursing Mothers: Pregnancy Category C.
NUCYNTA® ER should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus. Neonates born to mothers
physically dependent on opioids will also be
physically dependent and may exhibit respiratory
difficulties and withdrawal symptoms. Observe
newborns for symptoms of neonatal opioid
withdrawal syndrome. Withdrawal symptoms can
occur in breast-feeding infants when maternal
administration of NUCYNTA® ER is stopped.
Labor and Delivery: Opioids cross the placenta
and may produce respiratory depression in
neonates. NUCYNTA® ER is not for use in women
during and immediately prior to labor, when
shorter-acting analgesics or other analgesic
techniques are more appropriate.
Use in Elderly, Renal Impairment, and Hepatic
Impairment: See WARNINGS AND PRECAUTIONS.
DRUG ABUSE AND DEPENDENCE:
See BOXED WARNING
OVERDOSAGE: Institute supportive measures to
manage respiratory depression, circulatory shock,
and pulmonary edema as required. The opioid
antagonists, naloxone or nalmefene, are specific
antidotes to respiratory depression.
ADVERSE REACTIONS: In clinical studies, the
most common (≥10%) adverse reactions were
nausea, constipation, vomiting, dizziness,
somnolence, and headache.
Select Postmarketing Adverse Reactions:
Anaphylaxis, angioedema, and anaphylactic
shock have been reported very rarely with
ingredients contained in NUCYNTA® ER. Advise
patients how to recognize such reactions and
when to seek medical attention. Panic attack has
also been reported.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION
This does not include all the information needed to use NUCYNTA® ER safely and effectively.
See full Prescribing Information for NUCYNTA® ER.
INDICATIONS AND USAGE
NUCYNTA® ER is indicated for the management of:
• pain severe enough to require daily, around-the-clock, long-term opioid treatment and for
which alternative treatment options are inadequate
• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough
to require daily, around-the-clock, long-term opioid treatment and for which alternative
treatment options are inadequate.
Limitations of Usage
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended
doses, and because of the greater risks of overdose and death with extended-release opioid
formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment
options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not
tolerated, or would be otherwise inadequate to provide sufficient management of pain.
• NUCYNTA® ER is not indicated as an as-needed (prn) analgesic.
WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION;
ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND INTERACTION WITH
ALCOHOL
See full prescribing information for complete boxed warning.
• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to
overdose and death. Assess each patient’s risk before prescribing, and monitor regularly
for development of these behaviors or conditions. (5.1)
• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely,
especially upon initiation or following a dose increase. Instruct patients to swallow
NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2)
• Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose
of tapentadol. (5.2)
• Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid with-
drawal syndrome, which may be life-threatening if not recognized and treated. If opioid
use is required for a prolonged period in a pregnant woman, advise the patient of the risk
of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be
available. (5.3)
• Instruct patients not to consume alcohol or any products containing alcohol while taking
NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4)
CONTRAINDICATIONS
Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmon-
itored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus;
hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the
product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.
WARNINGS AND PRECAUTIONS
Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, a Schedule II controlled sub-
stance. As an opioid, NUCYNTA® ER exposes users to the risks of addiction, abuse, and misuse. As
modified-release products such as NUCYNTA® ER deliver the opioid over an extended period of
time, there is a greater risk for overdose and death due to the larger amount of tapentadol present.
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately
prescribed NUCYNTA® ER and in those who obtain the drug illicitly. Addiction can occur at recom-
mended doses and if the drug is misused or abused.
Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA® ER,
and monitor all patients receiving NUCYNTA® ER for the development of these behaviors or conditions.
Risks are increased in patients with a personal or family history of substance abuse (including drug or
alcohol addiction or abuse) or mental illness (e.g., major depression).The potential for these risks should
not, however, prevent the prescribing of NUCYNTA® ER for the proper management of pain in any given
patient. Patients at increased risk may be prescribed modified-release opioid formulations such as
NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper
use of NUCYNTA® ER along with intensive monitoring for signs of addiction, abuse, and misuse.
Abuse or misuse of NUCYNTA® ER by crushing, chewing, snorting, or injecting the dissolved product
will result in the uncontrolled delivery of tapentadol and can result in overdose and death.
Opioid agonists such as NUCYNTA® ER are sought by drug abusers and people with addiction dis-
orders and are subject to criminal diversion. Consider these risks when prescribing or dispensing
NUCYNTA® ER. Strategies to reduce these risks include prescribing the drug in the smallest ap-
propriate quantity and advising the patient on the proper disposal of unused drug. Contact local
state professional licensing board or state controlled substances authority for information on how to
prevent and detect abuse or diversion of this product.
Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depres-
sion has been reported with the use of modified release opioids, even when used as recommended.
Respiratory depression from opioid use, if not immediately recognized and treated, may lead to
respiratory arrest and death. Management of respiratory depression may include close observation,
supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Car-
bon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating
effects of opioids.
While serious, life-threatening, or fatal respiratory depression can occur at any time during the use
of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose increase.
Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA® ER and
following dose increases. To reduce the risk of respiratory depression, proper dosing and titration
of NUCYNTA® ER are essential. Overestimating the NUCYNTA® ER dose when converting patients
from another opioid product can result in fatal overdose with the first dose.
Accidental ingestion of even one dose of NUCYNTA® ER, especially by children, can result in
respiratory depression and death due to an overdose of tapentadol.
Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can
result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid with-
drawal syndrome in adults, may be life threatening if not recognized and treated, and requires
management according to protocols developed by neonatology experts. If opioid use is required for a
prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal
syndrome and ensure that appropriate treatment will be available.
Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pat-
tern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and
severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration
of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.
Interactions with Central Nervous System Depressants: Patients must not consume alcoholic
beverages or prescription or non-prescription products containing alcohol while on NUCYNTA® ER
therapy. The co-ingestion of alcohol with NUCYNTA® ER may result in increased plasma tapentadol
levels and a potentially fatal overdose of tapentadol.
Hypotension, profound sedation, coma, respiratory depression, and death may result if
NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depres-
sants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).
When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the
duration of use of the CNS depressant and the patient’s response, including the degree of toler-
ance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or
illicit drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made, start with
NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depres-
sion, and consider using a lower dose of the concomitant CNS depressant.
Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression
is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharma-
cokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor
such patients, particularly when initiating and titrating NUCYNTA® ER and when NUCYNTA® ER is
given concomitantly with other drugs that depress respiration.
Use in Patients with Chronic Pulmonary Disease: Monitor for respiratory depression those
patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients hav-
ing a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory
depression, particularly when initiating therapy and titrating with NUCYNTA® ER, as in these patients,
even usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the point of apnea.
Consider the use of alternative non-opioid analgesics in these patients if possible.
Hypotensive Effect: NUCYNTA® ER may cause severe hypotension. There is an increased risk
in patients whose ability to maintain blood pressure has already been compromised by
a reduced blood volume or concurrent administration of certain CNS depressant drugs
(e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension
after initiating or titrating the dose of NUCYNTA® ER. In patients with circulatory shock, NUCYNTA® ER
may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of
NUCYNTA® ER in patients with circulatory shock.
Use in Patients with Head Injury or Increased Intracranial Pressure: Monitor pa-
tients taking NUCYNTA® ER who may be susceptible to the intracranial effects of CO2 reten-
tion (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of
sedation and respiratory depression, particularly when initiating therapy with
NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can
further increase intracranial pressure. Opioids may also obscure the clinical course in a patient
with ahead injury.
Avoid the use of NUCYNTA® ER in patients with impaired consciousness or coma.
Seizures: NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure
disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol
in NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may in-
duce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure
disorders for worsened seizure control during NUCYNTA® ER therapy.
Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been report-
ed with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs
comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepineph-
rine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that
affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and
tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may
occur within the recommended dose. Serotonin syndrome may include mental-status changes
(e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood
pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or
gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.
Use in Patients with Gastrointestinal Conditions: NUCYNTA® ER is contraindicated in patients
with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause spasm
of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis,
for worsening symptoms.
Avoidance of Withdrawal: Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbu-
phine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received
or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA® ER. In
these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic
effect and/or may precipitate withdrawal symptoms.
When discontinuing NUCYNTA® ER, gradually taper the dose.
Driving and Operating Heavy Machinery: NUCYNTA® ER may impair the mental or physical abili-
ties needed to perform potentially hazardous activities such as driving a car or operating machinery.
Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of
NUCYNTA® ER and know how they will react to the medication.
Hepatic Impairment: A study with an immediate-release formulation of tapentadol in subjects with
hepatic impairment showed higher serum concentrations of tapentadol than in those with normal
hepatic function. Avoid use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce
the dose of NUCYNTA® ER in patients with moderate hepatic impairment. Closely monitor patients
with moderate hepatic impairment for respiratory and central nervous system depression when
initiating and titrating NUCYNTA® ER.
Renal Impairment: Use of NUCYNTA® ER in patients with severe renal impairment is not
recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The
clinical relevance of the elevated metabolite is not known.
ADVERSE REACTIONS
The following serious adverse reactions are discussed elsewhere in the labeling:
• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]
• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]
• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]
• Interaction with Other CNS Depressants [see Warnings and Precautions (5.4)]
• Hypotensive Effects [see Warnings and Precautions (5.7)]
• Gastrointestinal Effects [see Warnings and Precautions (5.11)]
• Seizures [see Warnings and Precautions (5.9)]
• Serotonin Syndrome [see Warnings and Precautions (5.10)]
Clinical Trial Experience
Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients
with Chronic Pain due to Low Back Pain or Osteoarthritis
The most common adverse reactions (reported by ≥10% in any NUCYNTA® ER dose group) were:
nausea, constipation, dizziness, headache, and somnolence.
The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled
studies reported by ≥1% in any NUCYNTA® ER dose group for NUCYNTA® ER- and placebo-treated
patients were nausea (4% vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2%
vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively.
Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients
with Neuropathic Pain Associated with Diabetic Peripheral Neuropathy
The most commonly reported ADRs (incidence ≥ 10% in NUCYNTA® ER-treated subjects) were:
nausea, constipation, vomiting, dizziness, somnolence, and headache.
Postmarketing Experience: The following adverse reactions, not above, have been identified
during post approval use of tapentadol. Because these reactions are reported voluntarily from
a population of uncertain size, it is not always possible to reliably estimate their frequency or
establish a causal relationship to drug exposure.
Psychiatric disorders: hallucination, suicidal ideation, panic attack.
Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients
contained in NUCYNTA® ER. Advise patients how to recognize such reactions and when to seek
medical attention.
DRUG INTERACTIONS
Alcohol: Concomitant use of alcohol with NUCYNTA® ER can result in an increase of tapentadol
plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume
alcoholic beverages or use prescription or non-prescription products containing alcohol while on
NUCYNTA® ER therapy.
Monoamine Oxidase Inhibitors: NUCYNTA® ER is contraindicated in patients who are receiving
monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to po-
tential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.
CNS Depressants: The concomitant use of NUCYNTA® ER with other CNS depressants includ-
ing sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and
alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor
patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression, sedation
and hypotension.
When combined therapy with any of the above medications is considered, the dose of one or both
agents should be reduced.
Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with the con-
comitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when
NUCYNTA® ER is coadministered with other drugs that may affect serotonergic neurotransmitter
systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® ER with
a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observa-
tion of the patient is advised, particularly during treatment initiation and dose increases.
Muscle Relaxants: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle
relaxants and produce an increased degree of respiratory depression. Monitor patients receiving
muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than
otherwise expected.
Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentaz-
ocine, nalbuphine, and butorphanol) and partial agonists (e.g., buprenorphine) may reduce the anal-
gesic effect of NUCYNTA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/
antagonist analgesics in patients receiving NUCYNTA® ER.
Anticholinergics: The use of NUCYNTA® ER with anticholinergic products may increase the risk of
urinary retention and/or severe constipation, which may lead to paralytic ileus.
USE IN SPECIFIC POPULATIONS
Pregnancy
Clinical Considerations
Fetal/neonatal adverse reactions
Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result
in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth.
Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding,
diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.
Teratogenic Effects - Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. NUCYNTA® ER should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in
neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter
acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can pro-
long labor through actions that temporarily reduce the strength, duration, and frequency of uterine
contractions. However this effect is not consistent and may be offset by an increased rate of cervical
dilatation, which tends to shorten labor.
Nursing Mothers: There is insufficient/limited information on the excretion of tapentadol in hu-
man or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on
tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded.
Because of the potential for adverse reactions in nursing infants from NUCYNTA® ER, a decision
should be made whether to discontinue nursing or discontinue the drug, taking into account the
importance of the drug to the mother.
Withdrawal symptoms can occur in breast-feeding infants when maternal administration of
NUCYNTA® ER is stopped.
Pediatric Use: The safety and efficacy of NUCYNTA® ER in pediatric patients less than 18 years of
age have not been established.
Geriatric Use: Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical
studies of NUCYNTA® ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75
years and over. No overall differences in effectiveness or tolerability were observed between these
patients and younger patients.
In general, recommended dosing for elderly patients with normal renal and hepatic function is
the same as for younger adult patients with normal renal and hepatic function. Because elderly
patients are more likely to have decreased renal and hepatic function, consideration should be given
to starting elderly patients with the lower range of recommended doses.
Renal Impairment: The safety and effectiveness of NUCYNTA® ER have not been established
in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® ER in patients
with severe renal impairment is not recommended due to accumulation of a metabolite formed
by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.
Hepatic Impairment: Administration of tapentadol resulted in higher exposures and serum levels
of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic
function. The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic impair-
ment (Child-Pugh Score 7 to 9).
Use of NUCYNTA® ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15).
DRUG ABUSE AND DEPENDENCE
Controlled Substance: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance
with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymor-
phone. NUCYNTA® ER can be abused and is subject to misuse, addiction, and criminal diversion. The
high drug content in the extended release formulation adds to the risk of adverse outcomes from
abuse and misuse.
Abuse: All patients treated with opioids require careful monitoring for signs of abuse and addic-
tion, because use of opioid analgesic products carries the risk of addiction even under appropriate
medical use.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even
once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited
to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the
use of steroids for performance enhancement and muscle build up.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after
repeated substance use and include: a strong desire to take the drug, difficulties in controlling its
use, persisting in its use despite harmful consequences, a higher priority given to drug use than to
other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking
tactics include emergency calls or visits near the end of office hours, refusal to under-
go appropriate examination, testing or referral, repeated claims of loss of prescriptions,
tampering with prescriptions and reluctance to provide prior medical records or contact
information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers)
to obtain additional prescriptions is common among drug abusers, and people suffering from
untreated addiction. Preoccupation with achieving pain relief can be appropriate behavior
in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians
should be aware that addiction may not be accompanied by concurrent tolerance and symptoms
of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true
addiction.
NUCYNTA® ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution.
Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests,
as required by law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and
proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Dependence: Both tolerance and physical dependence can develop during chronic
opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined
effect such as analgesia (in the absence of disease progression or other external
factors). Tolerance may occur to both the desired and undesired effects of drugs, and
may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant
dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs
with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pen-
tazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not
occur to a clinically significant degree until after several days to weeks of continued opioid usage.
NUCYNTA® ER should not be abruptly discontinued. If NUCYNTA® ER is abruptly discontinued in a
physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can
characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, pilo-
erection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps,
insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may
exhibit respiratory difficulties and withdrawal symptoms.
OVERDOSAGE
Clinical Presentation: Acute overdosage with opioids can be manifested by respiratory depres-
sion, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin,
constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked
mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.
Treatment of Overdose: In case of overdose, priorities are the re-establishment of a
patent and protected airway and institution of assisted or controlled ventilation if needed. Employ
other supportive measures (including oxygen, vasopressors) in the management of circulatory
shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life
support techniques.
Rx Only
© 2016 Depomed, Inc., Newark, CA 94560 USA
NUCYNTA® ER is a registered trademark of Depomed, Inc.
All rights reserved. APL-NUCX-0041 Rev.3
 EXECUTIVE EDITOR  KEVIN L. ZACHAROFF MD, FACPE, FACIP, FAAP

PUBLISHER  PAINWeek,  6 Erie Street, Montclair, NJ 07042

ART DIRECTOR  DARRYL FOSSA
EDITORIAL DIRECTOR  DEBRA WEINER
EDITOR  HOLLY CASTER

Charles E. Argoff  MD, CPE EDITORIAL BOARD Steven D. Passik  PhD

Professor of Neurology Senior Medical Director
Albany Medical College Endo Pharmaceuticals
Department of Neurology Malvern, PA
Director
Comprehensive Pain Center Peter A. Foreman  DDS, DAAPM John F. Peppin  DO, FACP
Albany Medical Center Consultant Medical Director, US Medical Affairs
Department of Neurology Rotorua Hospital and Private Practice Shionogi Inc.
Albany, NY Rotorua, New Zealand Florham Park, NJ

Paul Arnstein  RN , PhD, ACNS - BC , FNP-C, FAAN Gary W. Jay  MD, FAAPM , FACFEI Joseph V. Pergolizzi  MD
Clinical Nurse Specialist for Pain Relief Chief Officer Adjunct Assistant Professor
Massachusetts General Hospital AdviseClinical Johns Hopkins University School of Medicine
Boston, MA Raleigh, NC Department of Medicine
Baltimore, MD
Said R. Beydoun  MD, FAAN Mary Lynn McPherson  PharmD, BCPS, CPE, FASPE Senior Partner
Professor of Neurology Professor and Vice Chair Naples Anesthesia and Pain Medicine
Director of the Neuromuscular Program University of Maryland School of Pharmacy Naples, FL
Keck Medical Center of Department of Pharmacy Practice and Science
University of Southern California Hospice Consultant Pharmacist Robert W. Rothrock  PA -C, MPA
Los Angeles, CA Baltimore, MD University of Pennsylvania
Department of Anesthesiology and Critical Care
Jennifer Bolen  JD Srinivas Nalamachu  MD Pain Medicine Division
Founder Clinical Assistant Professor Philadelphia, PA
Legal Side of Pain Kansas University Medical Center
Knoxville, TN Department of Rehabilitation Medicine Michael E. Schatman  PhD, CPE, DASPE
Kansas City, KS Executive Director
Paul J. Christo  MD, MBA President and Medical Director Foundation for Ethics in Pain Care
Associate Professor International Clinical Research Institute Bellevue, WA
Johns Hopkins University School of Medicine Overland Park, KS
Department of Anesthesiology and Sanford M. Silverman  MD, PA
Critical Care Medicine Bruce D. Nicholson  MD CEO and Medical Director
Baltimore, MD Clinical Associate Professor Comprehensive Pain Medicine
Department of Anesthesia Pompano Beach, FL
Michael R. Clark  MD, MPH, MBA Penn State College of Medicine
Vice Chair, Clinical Affairs Hershey Medical Center Thomas B. Strouse  MD
Johns Hopkins University School of Medicine Hershey, PA Medical Director
Department of Psychiatry and Behavioral Sciences Director of Pain Specialists Stewart and Lynda Resnick
Director, Pain Treatment Programs Lehigh Valley Health Network Neuropsychiatric Hospital at UCLA
Johns Hopkins Medical Institutions Department of Anesthesiology Los Angeles, CA
Department of Psychiatry and Behavioral Sciences Allentown, PA
Baltimore, MD
Marco Pappagallo  MD
Geralyn Datz  PhD Director of Medical Intelligence
Affiliate Grünenthal USA
University of Southern Mississippi Bedminster, NJ
Department of Psychology Director
Clinical Director Pain Management & Medical Mentoring
Southern Behavioral Medicine Associates New Medical Home for Chronic Pain
Hattiesburg, MS New York, NY

Copyright © 2016, PAINWeek, a division of Tarsus Medical Group.

The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff.
PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume
any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from
reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the
reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

All rights are reserved by PAINWeek to accept, reject, or modify any advertisement submitted for publication. It is the policy of PAINWeek to not endorse products.
Any advertising herein may not be construed as an endorsement, either expressed or implied, of a product or service.

8 | PWJ | www.painweek.org Q4  | 2016
Global Education Group (Global) is accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education to physicians. Global Education Group designates
this live activity for a minimum of 36.0 AMA PRA Category 1 Credit(s)TM. This activity will be approved
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information and complete CME/CE accreditation details, visit our website at www.painweek.org.
 CONTENTS / PWJ / Q4 / 2016
12 | EXECUTIVE EDITOR’S LETTER 44 | COMPLEMENTARY&ALTERNATIVE
by kevin l. Zacharoff state of the art
PROLOTHERAPY REGENERATIVE MEDICINE
by donna d. Alderman 
FEATURES
18 | BEHAVIORAL SHORT CUTS
THE GENTLE ART OF SAYING NO
how to establish appropriate boundaries 53 | CLINICAL PEARLS
with pain patients by doug Gourlay
by david Cosio 
54 | ONE-MINUTE CLINICIAN
with jennifer Bolen ,  matthew Foster ,   ted Jones ,  
26 | PHARMACOTHERAPY michael Weaver
THE ROLE OF SPECIAL K IN
PAIN MANAGEMENT 55 | PAIN BY NUMBERS
by abigail Brooks / courtney Kominek

56 | PUNDIT PROFILE
36 | ADVANCED PRACTICE PROVIDER with paul j. Christo

THE ROLE OF THE ADVANCED PRACTICE

PROVIDER IN THE ACUTE CARE SETTING
by theresa Mallick-Searle

10 | PWJ | www.painweek.org Q4  | 2016
IN 2017 YOU CAN eXPeCT
TO eXPeRieNCe 120+ HOURS
OF COURSeS LiKe TH eSe:

www.painweek.org
 KEVIN L. research is needed, it’s important to know what options are available
ZACHAROFF in certain refractory cases, and what the future hopefully holds for
MD, FACPE, FACIP, FAAP this patient population. I’m betting that ketamine in subanesthetic
doses will be an important player in the future.

As we near the doorstep of 2017, I’m sure we all need to think a bit
more about the subject matter covered by Dr. David Cosio: the gentle
art of saying “No.” As I have mentioned countless times in my lec-
tures and articles, the patient-provider relationship is a critical piece
of the healthcare puzzle, especially in the management of chronic
pain. Dr. Cosio discusses the importance of the working alliance for all
stakeholders and the responsibilities that everyone shares. Somehow
in our culture, as I’m sure you all know, the prescription for medica-
tion has often become a sort of “trophy” for patients, with the prize
being a prescription pain medication. In a highly illustrative manner,

S
Dr. Cosio providers the reader with situations where the relationship
is the key ingredient in a safe and effective pain treatment plan, not
the medication.

Theresa Mallick-Searle has written an article about two things we—

and other pain related publications—probably don’t spend enough
time featuring: acute pain and the role of advanced practice health-
care providers in its management. In true frontline practitioner
fashion, Mallick-Searle presents a compassionate and cogent piece
that focuses on just how important adequate management of acute
pain is, especially in terms of the risk of developing chronic pain. I
can personally guarantee this article is one of those keep-on-hand
resources to help us think about the backstory to the undertreatment
of pain, and its consequences.
o much has happened this year in the world of chronic pain manage-
ment. As usual, much attention and discussion has focused on safe Lastly, but never least, is our Pundit Profile:Dr. Paul Christo. You will
and appropriate opioid prescribing. Indeed many debates were about gain insight into some of the amazing things Dr. Christo has done to
that particular subject. It is therefore fitting to me that the spirit of work towards the mission of “improving the lives of patients in pain
this final PWJ issue of the year covers other important approaches to through clinical care, education, and research.” No spoilers here—
managing chronic pain. read the profile to see what remarkable clinicians like Dr. Christo
do to contribute positively towards our profession and our patients.
Dr. Donna Alderman provides an in-depth and interesting look at pro-
lotherapy and its potential utility for treating patients with common As we leave 2016 behind, and in the spirit of this particular issue of
types of chronic pain related to musculoskeletal disorders and osteo- PWJ, let’s jointly make a commitment to heading towards the coming
arthritis. There were two aspects of this article that I found highly year with one common goal—the patient. Safety, efficacy, responsi-
compelling. First and foremost, that approaches like prolotherapy, bility, compassion, and open minds regarding appropriate treatment
along with other complementary and alternative treatments, are options are critical to achieving that commitment and goal. Have a
likely going to become increasingly important for practitioners to happy and healthy New Year!
consider when attempting to mitigate risks associated with other
therapies. Secondly, and equally as important, is that therapies which — KEVIN L. ZACHAROFF
help the body “heal itself” may indeed be keys to unlocking some of
the challenges associated with chronic pain and its treatment.

As an anesthesiologist, it gave me great pleasure to read the article Kevin L. Zacharoff, MD, FACPE, FACIP, FAAP, is Pain Educator and Consultant and
by Drs. Abigail Brooks and Courtney Kominek about a medication very Faculty, Clinical Instructor at SUNY Stony Brook School of Medicine, Department of
familiar to my specialty: ketamine, or “Special K.” The authors dis- Preventive Medicine, in Stony Brook, New York.
cuss its mechanism of action and potential role in helping to manage
challenging and often intractable types of chronic pain, such as com-
plex regional pain syndrome, cancer pain, and neuropathy. There
are many sides to ketamine’s risks and benefits and although more

12 | PWJ | www.painweek.org Q4  | 2016
Live Medical Conference 6.0–12.0 Ce/CMe credits
PAiNWeeKeND™ ReGiONAL CONFeReNCe SeRieS

PAiN 2017
MANAGeMeNT
FOR THe
MAiN STReeT
PRACTiTiONeR

painweekend.org

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ATLANTA GA HONOLULU HI PiTTSBURGH PA SeATTLe WA
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BiRMiNGHAM AL JACKSONViLLe FL RALeiGH- ST. LOUiS MO
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CiNCiNNATi OH MiLWAUKee WI SACRAMeNTO CA WOODCLiFF LAKe NJ
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This activity is provided by Global Education Group for 6.0–12.0 AMA PRA Category 1 Credits™.
This program is planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.
 ■
   Donna D. Alderman DO P.44
Donna Alderman is an expert in the field of musculoskeletal regenerative medicine. She is Board-Certified in pro-
lotherapy and has been practicing this nonsurgical treatment for musculoskeletal pain since 1996. Dr. Alderman is
Medical Director of the Hemwall Center for Orthopedic Regenerative Medicine, with two offices in California, and
can be reached via her website www.prolotherapy.com.

■
   Abigail Brooks PHARMD, BCPS P.26
Abigail Brooks is a Clinical Pharmacy Specialist in Pain Management, and Associate Director, PGY2 Pain & Palliative
Care Pharmacy Residency Program at the West Palm Beach VA Medical Center in Florida. Dr. Brooks coauthored
her article with Courtney Kominek, PharmD, BCPS, CPE, who is a Clinical Pharmacy Specialist in Pain Management
at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, Missouri.

■
   David Cosio PHD P.18
David Cosio is the psychologist in the Pain Clinic and the CARF-accredited, interdisciplinary pain program at the
Jesse Brown VA Medical Center, in Chicago. He received his PhD from Ohio University, with a specialization in
Health Psychology; completed a behavioral medicine internship at the University of Massachusetts-Amherst Mental
Health Services; and a Primary Care/Specialty Clinic Post-doctoral Fellowship at the Edward Hines Jr. VA Hospital.
Dr. Cosio has published several articles on health psychology, specifically in the area of patient pain education.

■
   Theresa Mallick-Searle MS, RN-BC, ANP-BC P.36
Theresa Mallick-Searle is an Adult Nurse Practitioner specializing in acute and chronic pain management at Stanford
Health Care in the Department of Pain Medicine, Palo Alto, California. As part of her commitment to bringing awareness
to the impact of unmanaged pain, she lectures nationally on topics surrounding both acute and chronic pain.

14 | PWJ | www.painweek.org Q4  | 2016
“Meetings
  come to an end, but learning never stops.
PWJ keeps you going all year long.” — Michael R. Clark Md, mph, mba
 ACCeSS
PAiNWeeK
365 DAYS
A YeAR
PAINWeek® is an innovative single point of access designed
specifically for frontline practitioners, recognized as a trusted
resource for the latest pain management news, information,
and education.
 
→Visit www.painweek.org to access key opinion leader insights
expressed via the following sections:

❶ Expert Opinion  ❷ Key Topics 

❸ One-Minute Clinician  ❹ Pundit Profile 
❺ PWJ—PAINWeek Journal 
The
gentle
art
of
saying

How to establish
appropriate boundaries
with pain patients

Cosio PHD
By David 
 e
B HAViORAL

abstract:Boundaries are simply rules or limits

that individuals create to identify reasonable, safe,
and permissible ways for others to behave around
them, and to determine how they’ll respond when
someone oversteps these boundaries.1 It is appar-
ent that pain management, in particular, requires
appropriate boundary setting—by the practitioner,
for the patient. This is crucial regardless of the
treatment plan, in part because providers often
find it hard to identify potential ruptures in their
relationships with patients.2,3 And sometimes, what
a patient may want may not be what they need, and
the practitioner saying “No” may be the therapy.
There is, however, a gentle art to saying “No.”

20 | PWJ | www.painweek.org Q4  | 2016
 “
  Patients who have rewarding
relationships with their
providers have better outcomes
and are less likely to seek
assistance from other sources,
which in turn reduces the
risk of conflicting treatment
plans and further confusion.”

Since the beginning of the new millennium, the field

of pain medicine has witnessed the pendulum of
change. At first, national organizations were directing
providers towards the use of opioid therapy in pain
management. About 5 decades ago, governments
around the world adopted the 1961 Single Convention
on Narcotic Drugs which, in addition to addressing the
control of illicit narcotics, obligated countries to work
towards universal access to the narcotic drugs deemed
necessary to alleviate pain and suffering. Henceforth,
effective pain management was deemed “a right to
health” according to international human rights law.4
As a consequence, patients believed they were entitled
to opioids, and providers felt pressured to provide
adequate treatment.5 As a result, this reinforced
patient’s beliefs and sole reliance on medications for
chronic pain management.6

Q4  | 2016 www.painweek.org  | PWJ | 21

BEHAVIORAL
“
 
T  oday, the health community and the general public
has witnessed how the sole reliance on narcotic medica-
tions has become an opioid epidemic.7 Politicians have even
started acknowledging the need for additional substance
use treatment centers in the United States to address the
problem. Approximately 80% of opioids are consumed in
the US alone, while most other countries do not rely as
much on these medications for pain management. This
overuse has led to an increase in prescription drug medica-
tion deaths, including some high profile individuals, such as
Anna Nicole Smith, Heath Ledger, and Prince.8 In March
2016, the Centers for Disease Control released new guide-
lines about the use of opioid medications for chronic pain
management in response to the crisis.9 This has caused a
lot of frustration among providers, as well as patients who
are seeking some relief from their chronic pain.
The Working Alliance
In reality, the right to effective pain management comes
with shared responsibilities between the patient and the pro-
vider.2 The benefits of building collaborations, or a “work-
ing alliance,” outweigh the challenges faced typically in the
exam room. This concept originated from psychology in the
1990s,10 and has been validated by strong research support.11
Patients at times are deemed “difficult” due to personality
conflicts, lack of trust, poor communication, cultural dif-
ferences, severe mental health/addiction concerns, cogni-
tive impairment, and/or concerns related to secondary gain.
Providers may also have common failures, including using
jargon, avoiding certain topics, making jokes, and acting like
a police officer, judge, or deal-maker. The working alliance
comes with some expectations: patients are expected to be
open, honest, obedient, motivated, and gracious, while pro-
viders are projected to be competent, thoughtful, empathic,
nonjudgmental, and good listeners.12,13 Remember, there are
22 | PWJ | www.painweek.org
…it is important to
recognize that a
boundary is not a
threat or an attempt to
control the behavior
of others, and that
setting appropriate
limits will ultimately
improve relationships
with patients.”
no difficult patients, just patients with difficulties. Patients
who have rewarding relationships with their providers have
better outcomes and are less likely to seek assistance from
other sources,11,14 which in turn reduces the risk of conflict-
ing treatment plans and further confusion. The success of
this working alliance often determines whether a patient
will adopt self-management strategies.6 Essential elements
of a healthy patient-provider relationship include compas-
sion, clear expectations (or boundaries), adequate expla-
nations on the provider side, and active participation and
involvement in decision-making on the part of the patient.15
Increased emphasis on communication has been proposed
as a way to improve the patient-provider relationship, and
communication training for providers has been shown to
be beneficial.14,15 There are 5 essential components to good
communication: really listening, expressing empathy, being
concise, asking questions and reflecting, and watching one’s
body language.
Setting Boundaries
Early on in my career, I worked with a young returning Vet-
eran who had come to the pain clinic asking to have his opi-
oids refilled. I remember discussing the risks and benefits of
the opioid medication with him, and educated him about the
comprehensive approach to pain management. The patient
seemed receptive and nodded his head, which I interpreted
as understanding and agreement. However, later that day I
received a call from his private psychologist arguing with
me about discouraging the use of his pain medications. The
patient apparently did not agree with the treatment plan and
had gone to him complaining of the care he received from
our clinic. I had to re-educate that provider about this new
approach and the need for him to provide a consistent mes-
sage to the patient. The patient was appropriately weaned
off the opiates in the pain clinic, but then he moved away to
Q4  | 2016
 another state and we lost contact. About a year later, I was [Name] “You are requesting a dose escalation for your opioid
at a concert venue and this individual approached me and medication and are reporting a decrease in physical activity.”
thanked me for what we had done for him. He admitted
being addicted to the opioid medication at that time, and said [Express] “The role of these medications is to assist you in being
we provided the boundaries for him to stop taking them— more active. The risks for these medications outweigh the benefits,
boundaries he could not hold himself. and I do not see any reason to continue them.”
Establishing appropriate boundaries is a skill that requires a
lot of thought and practice. Yet many providers have learned
little about it in medical school or clinical training. Ask
yourself, “Is it hard for me to say no? Do I take on patients’
problems or pain? Am I unable to tell people what I want, need,
or feel?” If you said “Yes” to any of those inquiries, then you
may have some difficulties setting boundaries. To master
this skill, it is important to recognize that a boundary is
not a threat or an attempt to control the behavior of others,
and that setting appropriate limits will ultimately improve
relationships with patients. There are 4 steps involved in
setting appropriate boundaries16:
1 Name or describe the behavior that is
unacceptable
2 Express what you need or expect from the patient
3 Decide what you will do if the patient does not
respect the boundaries you’ve established
4 Validate your actions by recognizing that setting
boundaries is important work and that your rights
are important
These skills can best be illustrated by common experiences
faced in pain clinics in the US, such as dealing with opioid
therapy.17
eXPeRieNCe #1
There are several tools providers may use, including opioid
risk assessment tools, pain opioid agreements, random urine
toxicology screens, state prescription monitoring programs,
decision trees, and patient pain education. An opioid risk
assessment tool, such as the Screener and Opioid Assessment for
Patients with Pain, or SOAPP, can be used to determine the extent
of monitoring required based on the patient’s relative risk for
developing problems when placed on long-term opioid therapy.18
Example: The patient presents with increasing pain complaints
and requests for opioid dose increases while reporting he/she
has decreased physical activity. There is no indication that opioid
therapy is helpful per your assessment. You could say:
Q4  | 2016
[Decide] “I would like you to complete this assessment tool.”
[The screener indicates the patient is at high risk and may need
additional monitoring or may not be a good candidate for opioid
therapy.] “The plan then will be to titrate the opioid down unless you
begin increasing your current level of exercise.”
[Validate] “In addition, I am going to refer you to physical therapy
for an assessment and will possibly add that treatment to your
current pain management plan.”
eXPeRieNCe #2
A pain care agreement, signed by both you and the patient,
helps patients understand the provider’s expectations, the
short-term nature of opioid therapy, the risks that may be
incurred, and the way various scenarios will be handled. For
example, a pain care agreement might outline how lost or
stolen opioids, requests for early refills, noncompliance with
scheduled appointments, and other aberrant behaviors
(eg, diversion, doctor/pharmacy shopping, violence and threats)
will be handled. As previously mentioned, it may also be useful
to consult the prescription drug monitoring electronic database,
which collects designated data on controlled substances
dispensed within participating states.
Example #1: The patient comes to your clinic as a walk-in and is
reporting someone has stolen their opioid medications. The patient
has shown up without a copy of the police report. You could then say:
[Name] “Today you came in as a walk-in and are reporting that
someone has stolen your opioid medications.”
[Express] “You, as the patient, have a shared responsibility for the
safety of these opioid medications.”
[Decide] “In accordance with the pain opioid agreement we both
signed, I will not refill that prescription without a copy of the police
report.”
[Validate] “In addition, with your permission, I plan to consult the
state prescription monitoring database.”
Example #2: The patient urgently calls you reporting an increase
in their pain and then shows up to your clinic for an unscheduled
appointment asking for an early refill. You could then say:
[Name] “Today you have shown up without a scheduled appoint-
ment reporting an increase in your pain.”
www.painweek.org  | PWJ | 23
BEHAVIORAL
[Express] “If the pain is emergent, you should seek treatment in
an emergency department or urgent care clinic.”
[Decide] “As outlined in the pain opioid agreement we both
signed, unscheduled visits are not to be used for opioid refills or
escalations.”
[Validate] “As my patient, you deserve to have a full visit and I
encourage you to schedule a follow-up appointment.”
eXPeRieNCe #3
A urine toxicology screen should be obtained regularly from
all chronic pain patients. If a patient tests positive for an illicit
substance (eg, cocaine, heroin, amphetamines, prescription
medications not prescribed), then a face-to-face discussion
outlining the conditions that must be met in order to initiate or
continue opioid therapy is crucial.
Example #1: You ordered a urine toxicology screen during your
patient’s last visit and it comes back either negative for a substance
you are prescribing or positive for a substance you did not prescribe.
You could then say:
[Name] “The results from your last urine tox screen indicate that
you are either not following your prescription and/or using illicit
substances/nonprescribed medications.”
[Express] “I am concerned about you and the safety of the
community. These medications are controlled substances and need
to be restricted. Would you consider seeking addiction services
to address your use of [insert illicit substance/nonprescribed
medication name here]?”
[Decide] “Would you agree to me conducting another urine tox
screen today?” [After the urine tox returns with the same result.]
“This is the second time this has occurred, and I will not be refilling
the opioid medication again.”
[Validate] “There is a concern that you may be diverting, sharing,
or self-escalating your dose of your medications.”
Example #2: The patient comes to your visit appearing
intoxicated or somnolent/ overmedicated. He/she also
continues to report taking his/her opiates as prescribed. You
could then say:
[Name] “I am concerned that the medications I prescribed
for you may be causing some sedation. Are you using more than
I prescribed or have you used any illicit substances today?”
[Express] “I am concerned about your safety as the patient and
the safety of the community. The opioid medication I am prescribing
is a controlled substance and we are both committed to making
sure you are taking them responsibly.”
24 | PWJ | www.painweek.org
[Decide] “I need to see your medication bottles in order to con-
duct a pill count. I also would like for you to have a urine tox screen.
Is it okay if I speak to your family about whether they have noticed
your sleepiness since taking this medication?”
[Validate] [The urine tox screen comes back positive for an illicit
substance and there may be safety concerns.] “I would also like to
consult with specialists in addiction services about your case or
refer you to the emergency department.”
eXPeRieNCe #4
Although there are complex guidelines for the management
of opioid therapy, simplified support tools, or “decision
trees,” can guide providers through difficult discussions and
assist in determining a course of treatment for chronic pain
patients.19 Using these tools will present an opportunity for
providers to educate patients about the range of nonopioid pain
management strategies that are available, attempt to integrate
patient preferences, and encourage joint decision-making.
It may also be helpful to expand the conversation to include
treatment outcomes that do not focus solely on the reduction
or control of pain but also on effective functioning within the
context of continued pain.11
Example: The patient is upset and making suicidal/homicidal
threats after being told opiate therapy is being discontinued at this
time. You could then say:
[Name] “It is my understanding that you are making threats to
yourself [or someone else].”
[Express] “I am concerned about your safety [or the safety of the
specified individual or the community at large].”
[Decide] “I have a duty to warn, so I am going to page a psycholo-
gist [or call the police for assistance or escort you to the emergency
department].”
[Validate] “I am also planning to consult with the other providers
on the pain clinic team about your case.”
Maximizing Safety/Minimizing Risk
Especially in cases involving opioid therapy, it is important
to establish boundaries early on, be consistent with your
message, document the restrictions made, use policy and
procedures as backup, review the pain opioid agreement,
and use other tools available. The most common concern
expressed by providers working in chronic pain manage-
ment is how to handle patient refusals. It is important to
Q4  | 2016
 remember that it is the patient’s decision and right, and that
they need to take responsibility for their choices. Providers
should avoid making decisions based on emotions instead of
facts. Providers are not obligated to provide opioid therapy,
but are obligated to provide the best level of clinical care as
outlined by the 1961 Single Convention on Narcotic Drugs.
The goal for providers should always be to maximize safety
and minimize risk for the patient and the community at large.
Therefore, efforts should be shifted from simply rejection to
redirection—pointing people in a healthier direction.
Providers are in the best position to educate and coach
patients who suffer from chronic pain about all the different
types of nonopioid treatments available for pain manage-
ment. Essentially, providers are trying to put pain man-
agement back into the patient’s hands. There are 4 general
classifications to these treatments:
1 Traditional medical treatments: nonopioid
medications, injections/procedures, recreation,
and physical medicine and rehabilitation
2 Psychological interventions: hypnosis, biofeed-
back, cognitive behavioral therapies, and mindful-
ness based therapies
3 Complementary and alternative medicine modal-
ities: acupuncture, relaxation, spinal manipulation,
healing touch, and massage therapy
4 Adjustment to lifestyle imbalances caused by
the pain: nutrition, sleep hygiene, mental health,
physical activity, weight gain, sexual health,
vocational rehabilitation, and spiritual needs
Conclusion
Clinical trials have indicated the comparable efficacy of the
treatments mentioned above.20 Overall, the current evidence
provides little support for choosing one treatment approach
over another. The provider and the patient have to determine
what’s best for the patient. It’s important to note that using
these other options as opposed to opioid therapy is better for
everybody—the patient, the provider, and the community
at large. Remember, saying “No” to opioid therapy remains
one of those options. 
References
1. Walters G. Boundaries. Out of the Fog. Available at: outofthefog.net/
CommonNonBehaviors/Boundaries.html.
2. Gourlay DL , Heit HA . Pain and addiction: Managing risk through
comprehensive care. J Addict Dis. 2008;27:23–30.
3. Gourlay DL , Heit HA , Almahrezi A. Universal precautions in pain
Q4  | 2016
medicine: a rational approach to the treatment of chronic pain. Pain Med.
2005;6:107–112.
4. Hall J, Boswell M. Ethics, law, and pain management as a patient
right. Pain Physician. 2009;12:499–506.
5. Zgierska A, Miller M, Rabago D. Patient satisfaction, prescrip-
tion drug abuse, and potential unintended consequences. JAMA .
2012;307:1377–1378.
6. Dorflinger L, Kerns R, Auerbach S. Providers’ roles in enhancing
patients’ adherence to pain self management. Transl Behav Med.
2013;3:39–46.
7. Centers for Disease Control and Prevention. Drug overdose
in the United States: fact sheet. 2013. Available at: www.cdc.gov/
homeandrecreationalsafety/overdose/facts.html.
8. Ives T, Chelminski P, Hammett-Stabler C, et al. Predictors of opioid
misuse in patients with chronic pain: a prospective cohort study. BMC
Health Serv Res. 2006;6:46.
9. Centers for Disease Control and Prevention. Guideline for prescribing
opioids for chronic pain— United States 2016. Recommendations and
Reports. 2016;65(1):1–49.
10. Bordin E. The generalizability of the psychoanalytic concept of the
working alliance. Psychother Theory Res Pract. 1979;16:252–260.
11. Vowles K, Thompson M. The patient-provider relationship in chronic
pain. Curr Pain Headache Rep. 2012;16:133–138.
12. Bergman A, Matthias M, Coffing J, et al. Contrasting tensions
between patients and PCPs in chronic pain management: a qualitative
study. Pain Med. 2013;14:1689–1697.
13. Gulbrandsen P, Madsen H, Benth J, et al. Health care providers
communicate less well with patients with chronic low back pain: a study of
encounters at a back pain clinic in Denmark. Pain. 2010;150:458–461.
14. Frantsve L, Kerns R. Patient-provider interactions in the management
of chronic pain: Current findings within the context of shared medical
decision making. Pain Med. 2007; 8:25–35.
15. Street R, Makoul G, Arora N, et al. How does communication heal?
Pathways linking clinician-patient communication to health outcomes.
Patient Educ Couns. 2009;74:295–301.
16. Setting personal boundaries. Learning and Violence. Available at:
www.learningandviolence.net/violence/disclosure/boundaries.pdf.
17. Robeck I. Introduction: it’s never too late to start all over again.
Available at: www.painedu.org/articles_timely.asp?ArticleNumber=50.
18. Inflexxion. Screener and Opioid Assessment for Patients with Pain
(SOAPP). Available at: www.pain.edu.org/soapp.asp.
19. Cosio D. How to set boundaries with chronic pain patients.
J Fam Pract. 2014;63:S3-S8.
20. Keller A, Hayden J, Bombardier C, et al. Effect sizes of non-surgical
treatments of non-specific low-back pain. Euro Spine J. 2007;16:1776–1788.
www.painweek.org  | PWJ | 25
the role of
special

in pain management Brooks PHarmD, bcps

By Abigail 

Courtney Kominek PHARMD, BCPS, CPE

Special K refers to
one of the many
street names for
ketamine when
used illicitly via
various routes for
its dissociative and
hallucinatory effects.
 PHARMACOTH RAPY e

abstract: Ketamine, known on the street as “special K,” is a dissociative an-

esthetic with hallucinogenic properties and is classified as a controlled sub-
stance. Its unique mechanism as an N-methyl-D-aspartate (NMDA) receptor
antagonist is thought to be responsible for many of the drug’s most promising
properties. Stimulation of the NMDA receptor results in central sensitization
(wind up phenomenon), hyperalgesia, reduced sensitivity to opioids, and the
development of opioid tolerance. This can result in allodynia, hyperalgesia,
and prolonged pain response. Ketamine partially reverses the previously men-
tioned complications that can restore the effectiveness of opioids in various
settings and often allows for reduced opioid doses and improved pain con-
trol. With appropriate clinical knowledge and patient monitoring, ketamine at
subanesthetic doses can play a role in the treatment of complex regional pain
syndrome (CRPS), cancer pain, and even neuropathic or chronic pain refrac-
tory to typical treatment options. Depending on the clinical setting, ketamine
can be administered via intravenous (IV ) or oral (PO) routes, among others.
Clinical monitoring is required to ensure that side effects, such as dysphoria,
do not adversely impact the patient.

28 | PWJ | www.painweek.org Q4  | 2016
 With appropriate clinical knowledge
and patient monitoring, ketamine at
subanesthetic doses can play a role
in the treatment of complex regional
pain syndrome, cancer pain, and even
neuropathic or chronic pain refractory
to typical treatment options.

INTRODUCTION Also, ketamine activates the descending pain pathway.1

Ketamine, an anesthetic structurally related to phencycli- Dopamine and serotonin reuptake are inhibited, and there
dine (PCP), is a Schedule III controlled substance, according are increased levels of epinephrine and norepinephrine.3
to the Controlled Substances Act, that has both licit and The anti-inflammatory effects of ketamine are unclear and
illicit uses.1,2 Special K refers to one of the many street names additional studies are needed on the potential anti-tumor
for ketamine when used illicitly via various routes for its effects of ketamine.6 Table 1 lists some of the proposed indi-
dissociative and hallucinatory effects.2 In addition to its dis- cations for the use of ketamine, including several nonpain
sociative anesthetic properties, ketamine also has analgesic, related conditions.1
sedative, and amnesic characteristics.2,3 Anesthetic doses of
ketamine range from 0.5 to 4.5 mg/kg/h while subanesthetic
doses are generally in the range of 0.1 to 0.3 mg/kg/h.4 This
article reviews the use of ketamine at subanesthetic doses in CONTRAINDICATIONS
pain management, as presented at PAINWeek 2016. There are some situations in which ketamine is contra-
indicated. Absolute contraindications include uncontrolled
seizure disorder, severe symptoms related to increased intra-
cranial pressure, active psychosis, or previous adverse reac-
MECHANISM OF ACTION tion to ketamine. Uncontrolled hypertension, congestive
Though ketamine interacts with multiple receptors in heart failure, recent stroke, severe neurologic impairment,
the central and peripheral nervous systems, ketamine’s and a history of psychosis are relative contraindications.4,8
primary mechanism of action is through noncompetitive
NMDA receptor antagonism. This reduces the release of
the excitatory neurotransmitter, glutamate, involved in
afferent pain transmission.5 It is through the antagonistic ROUTES OF
effects on NMDA receptors that ketamine is thought ADMINISTRATION
to reverse hyperalgesia, opioid tolerance, and central Several routes are available for the administration of ket-
sensitization.3,6 amine including IV, PO, intramuscular ( IM ), subcutaneous
(subQ), intranasal, and topical.7,9 Typically, the IM route
In addition, ketamine binds to mu-, kappa-, and delta-opioid is discouraged for pain management due to the discomfort
receptors. Hirota et al 1996 suggested that ketamine is a associated with the injection. The subQ route can be irritat-
mu-opioid receptor antagonist and a kappa-opioid receptor ing and require frequent rotation of injection sites.3,8 There
agonist.5 Later in 2011 Hirota et al proposed that ketamine is no oral formulation available, so the injectable formulation
is a mu-opioid receptor antagonist and a kappa-receptor is used orally.3,7 This has a bitter taste so it is usually mixed
antagonist at anesthetic doses.6 However, others classify with juice, soda, or gelatin.3,7 Preservative induced neurotox-
ketamine as a mu-opioid receptor agonist.7 The analgesic icity can occur with intrathecal administration, and as the
effect of ketamine is stereoselective with the S(+)-enantio- preservative-free formulation is not available in the United
mer yielding more analgesia than the R(-)-enantiomer.6 States, intrathecal administration should be avoided.7,9

Q4  | 2016 www.painweek.org  | PWJ | 29

PHARMACOTHERAPY

Table 1. Proposed Indications for Ketamine1

Opioid induced hyperalgesia

Complex regional pain syndrome
Neuropathic pain
Posttraumatic stress disorder
Migraine headaches
Depression
Trauma pain
Anxiety
Malignant pain
Burn pain
Opioid refractory pain
Bipolar depression
Chronic pain
Abdominal pain
Hospice
Fibromyalgia
Postoperative pain

PHARMACOKINETICS effects—such as auditory hallucinations, paranoia, anxi-

There is a significant hepatic first pass effect with oral
administration of ketamine leading to delayed and incom-
plete absorption.7 Due to its high lipid solubility, ket-
amine rapidly crosses the blood brain barrier.1,3 When
injectable formulation is given orally, the onset of effect is
30 minutes, duration of action is 4 to 6 hours, and half-life
is 3 hours.10 The half-life of IV ketamine is 2 to 3 hours
with a duration of analgesia of about 2 to 6 hours.3 With
long-term infusions of ketamine, the duration of infusion
determines the half-life, with an estimated half-life of
11 days in complex regional pain syndrome Type 1 patients.1
Ketamine is metabolized through cytochrome P450 (CYP)
2B6, CYP2C9, and CYP3A4 via N-demethylation to nor-
ketamine, an active metabolite, with one-third the analge-
sic potency of its parent.1 Elimination occurs through the
kidney and bile.1
ety, inability to control thoughts, derealization in time and
space, and increased awareness of sound and color—are
dose related though may occur at even low doses used for
pain.1,3 With the discontinuation of ketamine, the psycho-
mimetic effects quickly disappear.1 Ketamine may also con-
tribute to memory and cognitive impairment that typically
resolves with short-term use though data with long-term
use is not available.1
Cardiovascular effects are another concern with ketamine
use. Low dose ketamine leads to cardiac stimulation mostly
through sympathetic nervous system activation. Tachycar-
dia, systemic or pulmonary hypertension, increased cardiac
output, and increased myocardial oxygen consumption may
ensue. Therefore, monitoring of vitals is essential when
administering low dose ketamine for pain.1

Hepatic effects involve elevation in the liver enzyme pro-

file including alanine transaminase, alkaline phosphatase,
ADVERSE EFFECTS aspartate transaminase, and gamma-glutamyl transferase.
The adverse effects of ketamine fall into 3 main groups: The risk of hepatotoxicity increases with prolonged or
central nervous system (CNS), cardiovascular, and hepatic.1 repeated exposures to ketamine in a short period of time.
CNS effects include psychomimetic as well as dizziness, With cessation of ketamine, the liver enzyme profile typi-
blurred vision, nightmares, and others. Psychomimetic cally normalizes within 3 months.1

30 | PWJ | www.painweek.org Q4  | 2016
 Table 2. Example Patient Monitoring Parameters*
Heart Rate Blood Pressure Respiratory Rate

Fitzgibbons »» Monitor 30 minutes after initial »» Monitor 30 minutes after initial Monitor 30 minutes after initial
20054 dose and each dose increase dose and each dose increase dose and each dose increase
»» Subsequent monitoring every »» Subsequent monitoring as
4 hours or as clinically required clinically required

National Health Service, »» Check baseline pulse
Scotland
»» Check 1 hour after first dose
20138
»» Check 24 hours after first dose
»» Check daily
»» If pulse increases to ≥20 bpm
or >100 bpm, inform provider
»» Check baseline BP If RR decreases to 10 breaths/
minute, inform provider
»» Check 1 hour after first dose
»» Check 24 hours after first dose
»» Check daily
»» If BP increases ≥20 mm Hg
above baseline, notify provider

 *Monitoring parameters vary depending on the protocol

Monitoring parameters vary depending on the protocol. Association for the Study of Pain ( IASP) has diagnostic crite-
Table 2 provides examples of the monitoring parameters of ria for CRPS that requires “the presence of initiating noxious
2 protocols.4,8 Adverse effects of ketamine can be managed event or cause of immobilization; continuing pain, allodynia,
in various ways. To prevent opioid toxicity due to the res- or hyperalgesia, with which the pain is disproportionate to
toration of opioid sensitivity, it is recommended to reduce any inciting event; evidence at some time of edema, changes
opioid dose by 25% to 50% upon initiation of ketamine.3,4 in skin blood flow, or abnormal sudomotor activity in the
CNS adverse effects can be managed with reducing the region of pain; and the diagnosis is excluded by the existence
dose, slowing the titration of medication, or treatment of of conditions that would otherwise account for the degree
symptoms.3 Benzodiazepines, antipsychotics, propofol, and of pain and dysfunction.”13 CRPS can be categorized into
clonidine have been used to mitigate CNS adverse effects.1,3 Type 1 or Type 2 based on the absence or presence of clinical
Cardiovascular effects are managed through ketamine dose signs of major peripheral nerve injury, respectively.12 The
reduction.1 Budapest Criteria was developed to address limitations with
the IASP CRPS diagnostic criteria; however, most of the
The cost of a ketamine infusion can be substantial. Since literature discussed in this article utilizes the IASP CRPS
ketamine is being used in an off-label fashion, patients are diagnostic criteria.14
generally paying out-of-pocket. Data from 2015 suggests a
ketamine infusion can range in price from $400 to $1700 Sigtermans and colleagues15 conducted a randomized,
per infusion.11 double-blind, placebo-controlled, parallel-group trial
in 60 patients with CRPS -1 based on IASP criteria.
Patients received either a 4.2-day IV infusion of low-dose
S(+)-ketamine or placebo (normal saline). Ketamine was
KETAMINE initiated at 1.2 mcg/kg/min and titrated based on tolerability
AND COMPLEX REGIONAL and effect up to a maximum of 7.2 mcg/kg/min. The primary
PAIN SYNDROME (CRPS) outcome was pain scores reported via numerical rating scale
CRPS, previously known as reflex sympathetic dystrophy ( NRS) from 0 to 10 at baseline and weekly until week 12.
(RSD), was first recognized in the American Civil War. It has Results showed that ketamine led to a statistically significant
an incidence rate of 5.46 to 26.2 per 100,000 persons.12 The reduction (P<0.001) in pain compared to placebo during the
hallmark of CRPS is central sensitization. The International 12-week study, but the significance was lost at week 12. There

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PHARMACOTHERAPY

was no statistically significant change in function with ket- case reports, clinical experience, etc.] Examined research
amine. Adverse effects were common, with 93% of ketamine incorporated many different routes of administration, doses,
patients compared to 17% of placebo patients experiencing and outcome measures. There were also variable inclusion
psychomimetic effects. Nausea (63% ketamine vs 17% pla- and exclusion criteria. Other concerns with the literature
cebo), vomiting (47% vs 10%), and headache (37% vs 33%) were the relatively small sample sizes involved and large
were also reported. Only 2 patients discontinued the study placebo response observed. Due to wide range in treatment
due to psychomimetic effects.15 duration and doses utilized, the authors were unable to com-
ment on the most effective route or dose. There were also
Another double-blind, randomized, placebo-controlled concerns with safety and tolerability because of the side
study was completed by Schwartzman and colleagues.16 effect profile. Overall, it was determined that evidence is
The investigators planned to enroll 40 patients in the study. inconclusive and only weak evidence exists for the use of
Enrollment was discontinued after 19 patients because ketamine in CRPS. Ketamine is not considered a first-line
an interim analysis showed little placebo effect and the treatment option in CRPS.9 Further rigorous research is
researchers had increased experience and efficacy with recommended.18
higher doses of ketamine (50 mg/h). Patients were included
if they had a diagnosis of CRPS based on IASP criteria. A
4-hour infusion for 10 days of low dose ketamine or placebo
(normal saline) was administered to patients according to KETAMINE
the following schedule: 5 days on, 2 days off, and 5 days AND MALIGNANT PAIN
on. Ketamine was titrated up to a maximum 0.35 mg/kg/h. The National Comprehensive Cancer Network ( NCCN )
Patients also received midazolam and clonidine. Overall, guidelines reiterate that pain management is an essential
there was statistically significant reductions in pain in the component of oncologic management and that adequate pain
ketamine group compared to placebo (P<0.01), but there management positively contributes to quality of life improve-
was no change in the level of activity when comparing pre- ment, most likely for both the patient and the patient’s loved
and posttreatment values. There was a statistically signif- ones.19 Regarding the use of ketamine in malignant pain, the
icant reduction in nighttime awakenings in the ketamine following studies and publications were highlighted during
group compared to placebo (P<0.05). No patients in the the PAINWeek 2016 presentation.
study reported agitation, blurred vision, or psychomimetic
effects, but 6 of 19 patients experienced nausea, headache, The randomized, double-blind, placebo-controlled trial
tiredness, or dysphoria (4/9 in ketamine group, 2/10 in pla- by Salas and colleagues20 investigated the use of ketamine
cebo group).16 continuous IV infusion (CIVI ) in combination with mor-
phine IV compared to placebo CIVI with morphine IV for
Noppers and colleagues17 reported on drug induced liver the treatment of cancer pain refractory to standard opioids
injury with ketamine treatment for CRPS -1 based on IASP (defined as pain score ≥4/10 after 24 hours of morphine
criteria. There were 6 patients enrolled in the group who CIVI ). The patients (N=20; 11 ketamine, 9 placebo) were
were to receive 100 hour infusions of S(+)-ketamine twice treated at a group of adult palliative care units in the south
separated by 16 days. Ketamine was initiated at 1.2 mcg/ of France. Neither group had a predefined maximum dose
kg/h and titrated to a maximum of 7.2 mcg/kg/h. All but for morphine IV; for ketamine treatment, therapy was ini-
one patient in this group experienced a side effect, including tiated at 0.5 mg/kg/day then increased to 1 mg/kg/day after
hypertension (n=1), psychotropic side effects (n=1), or hep- 24 hours if the pain score remained ≥1/10. Patients were
atotoxicity (n=3). All patients affected with hepatotoxicity evaluated and reassessed at the following time points: ran-
received 2 exposures to ketamine within a 4-week interval. domization (baseline), at ketamine or placebo start time (T0),
Within 2 months of ketamine treatment discontinuation, and at 2 hours (T1), 24 hours (T2), and 48 hours (T3) after
liver enzymes normalized. Those who received ketamine T0. The primary outcome of the study was to assess the
at longer intervals did not experience hepatotoxicity. These change in the pain score between baseline and T1 (2 hours
findings support the regular monitoring of liver function after baseline evaluation). The results of the study found that
with ketamine.17 self-reported pain scores did not differ significantly between
the 2 groups, regardless of time points compared (T2 change
A systematic review of ketamine for CRPS was performed by from T0, T3 change from T0). With the use of ketamine,
Connolly and colleagues.9 Many more articles from level III morphine consumption did not decrease during the study
evidence (n=13) and level IV evidence (n=21) were included period; in fact, morphine doses were not different between
compared to level I evidence (n=6) and level II evidence (n=5) the ketamine and placebo groups. In addition, no difference
because of the lack of availability in the literature. [Level I: was found between the groups in analgesic effect, tolerabil-
meta-analysis or systematic reviews. Level II: ≥1 well-pow- ity, or patient satisfaction. Overall, the study authors were
ered randomized, controlled trial(s). Level III: retrospective unable to conclude that a ketamine-morphine combination
studies, open-label trials, pilot studies. Level IV: anecdotes, provides superior pain relief compared to morphine alone.20

32 | PWJ | www.painweek.org Q4  | 2016
 The Cochrane Review concluded
that the current evidence is insufficient
to assess the benefits and harms of
ketamine as an adjuvant to opioids for
cancer pain and that more randomized
controlled trials are needed to investigate
its use.

In another randomized, double-blind, placebo-controlled colleagues7 identified a total of 5 randomized controlled

study by Hardy and colleagues,21 study authors investigated trials, 6 prospective nonrandomized, uncontrolled trials, and
the use of subQ ketamine for malignant pain refractory to 1 retrospective review investigating the use of ketamine in
standard opioids and coadjuvants at predefined dose levels adults with cancer pain. While the review also included data
(pain score ≥3/10). Over a 5-day time frame, ketamine vs on the use of ketamine in children, the presenters focused
placebo (normal saline) was administered to the study patient on the adult data. In all, the various trials included a total
population (N=187; 149 met definition of completion). Ket- of N=483 and, due to heterogeneity, direct comparison of
amine was initiated at 100 mg/24 hours and titrated up to a trials was not feasible. The routes of administration for ket-
maximum dose of 500 mg/24 hours; if 80% of study drug had amine included IV, PO, subQ, intrathecal, and sublingual;
been delivered and average pain improved by ≥2 units with the authors identified recommended ketamine infusion dos-
no more than 4 breakthrough doses, the study drug dose ages ranging from 0.05 to 0.5 mg/kg/h ( IV or subQ). In
remained the same. The primary outcome was clinically addition, recommended oral dosages of ketamine range from
relevant improvement in pain—defined as reduction in pain 0.2 to 0.5 mg/kg 2 to 3 times per day with a maximum dose
score by ≥2 points from baseline in the absence of more than of ketamine 50 mg PO three times a day for long-term use.
4 breakthrough doses of analgesia over prior 24 hours—at The authors also advised that intrathecal ketamine infusion
the end of the 5-day study period. The final results found no should be avoided due to 2 case reports of spinal cord necrosis
difference in outcome in study patients who met the defi- on autopsy. Limitations identified in the literature presented
nition of completion, in the subgroup that received 5 days and reviewed include the small number of total studies, few
of study drug, or when all participants with baseline pain blinded randomized controlled trials, small sample sizes, and
scores were included. In fact, no significant difference was short duration of follow-up compared to the chronic nature
noted with multiple analysis methods though the manuscript of the pain. Overall, the review concluded that ketamine
did report a number-needed-to-treat ( NNT ) and a number- should be considered as an adjuvant for refractory cancer
needed-to-harm ( NNH ). The subQ route of administration pain though also called for additional research.7
is not recommended, as evidenced by this study which found
that injection site reactions were significantly more likely to
occur in the ketamine group (P<0.001).21
KETAMINE AND
In the 2012 update to the 2003 Cochrane Review of ketamine NEUROPATHIC PAIN
as an adjuvant to opioids for cancer pain, no new identi- Neuropathic pain can be challenging to manage and treat
fied studies were included in the final review. Overall, the as the cause can be related to an injury, such as spinal cord
Cochrane Review concluded that the current evidence is injury, or postsurgical, or due to a more chronic condition,
insufficient to assess the benefits and harms of ketamine as an such as poorly controlled diabetes or herpes zoster. The
adjuvant to opioids for cancer pain and that more randomized most complex patients can experience pain that is refrac-
controlled trials are needed to investigate its use.22 In another tory to treatment with multimodal therapy and/or high-
systemic review and synthesis of the literature, Bredlau and dose opioids. A 5-year retrospective, nonrandomized study

Q4  | 2016 www.painweek.org  | PWJ | 33

PHARMACOTHERAPY
The potential
future for
ketamine seems
bright with
possibility.
conducted by Marchetti and colleagues23 investigated the
use of ketamine for the treatment of refractory chronic pain
conditions, including neuropathic pain that was postsurgical
in nature or related to fibromyalgia or other miscellaneous
conditions (60% of the study population, N=55 cases with 4
patients undergoing 2 separate treatments each). Ketamine
was initiated via IV in the hospital and then converted to
PO for continued use as an outpatient; however, with time, a
simpler process was adopted. In the simpler process, patients
were admitted for a 1-day hospitalization and IV ketamine
infusion before conversion to PO route and others were
simply started on PO ketamine as an outpatient. The max-
imum dose of PO ketamine that patients could titrate to
was 3 mg/kg/day over the course of 1 to 3 months, and then
patients were gradually tapered down to limit withdrawal
symptoms from ketamine use. In patients prescribed opi-
oids upon initiation of ketamine, the opioid daily dose was
reduced. Several pieces of key information were tracked
over the course of the study to categorize patients into 1 of
4 groups: effective (mean pain reduction ≥50% and/or qual-
ity of life significantly improved); partially effective (mean
pain reduction 25% to 50%); opioid sparing only (mean pain
reduction <25%, but opioid dose decreased by ≥30%); or fail-
ure (mean pain reduction ≤25%, quality of life not improved,
and opioid dosage not decreased). Final results found PO
ketamine to be effective in 44% of patients, partially effec-
tive in 20%, opioid sparing only in 14%, and completely
ineffective or failure in 22%. Interestingly, patients without
any opioid treatment during the ketamine challenge showed
a 36% failure rate, whereas those receiving opioids showed
only a 7% failure rate (P<0.02), suggesting that ketamine is
an adjuvant to opioids rather than a stand-alone treatment.
Most importantly, at the end of treatment when ketamine
decreased pain intensity (P<0.05), those patients were more
often working and less often off work,23 a unique finding
as other studies did not necessarily report improvement in
function in terms of work attendance.
34 | PWJ | www.painweek.org
In a literature review for the pharmacologic treatment of
neuropathic pain associated with spinal cord injury, 3 ket-
amine studies were briefly reviewed. Two of the studies used
ketamine administered via IV in combination with another
drug (gabapentin and alfentanil, respectively) while the third
compared ketamine to lidocaine. In summary, ketamine was
found to be effective for pain, though it is uncertain how long
this analgesic response lasts. Further studies are needed.24 A
less conventional use of ketamine is the topical application
for neuropathic pain. Case reports on the use of topical ket-
amine for pain relief started being published in the 1990s,
and efficacy is thought to be related to activity at glutamate
receptors on peripheral nerve endings. A literature review
published by Sawynok 25 identified both plain ketamine top-
ical application as well as topical ketamine in combination
with various other ingredients, including but not limited to
amitriptyline, baclofen, lidocaine, clonidine, ketoprofen, and
gabapentin. Topical ketamine products investigated ranged
in concentration from 0.5% to 10%; while acute topical
application of ketamine at these concentrations produced
no detectable levels of ketamine or active metabolite in the
plasma. There is no data after repeated doses and higher
concentrations of ketamine.25 Though bypassing the poten-
tial side effects associated with systemic administration of
ketamine, topical ketamine may be difficult to find at a local
compounding pharmacy or may be cost prohibitive to the
patient. Again, further research is needed to determine the
most appropriate patient for topical ketamine application.
THE FUTURE OF SPECIAL K
Ketamine continues to be an area of interest and devel-
opment in the clinical world, including but not limited to
pain management. In particular, at least 2 pharmaceutical
companies are studying and developing ketamine-like drugs.
Janssen Pharmaceuticals is in late-stage trials of esketamine,
Q4  | 2016
 a ketamine variant which can be administered via nasal spray.
This product was granted Breakthrough Therapy Designa-
tion by the U.S. Food and Drug Administration in 2013 for
treatment-resistant depression and then again in 2016 for
major depressive disorder with imminent risk of suicide.11,26
In addition, Naurex Inc., is currently working on GLYX-13,
an IV glycine-site functional partial agonist (GFPA) selective
modulator of the NMDA receptor that lacks ketamine’s dis-
sociative side effects for treatment-resistant depression.11,27
As of September 2016, there were 172 studies that were open
and not yet recruiting or open and actively recruiting inves-
tigating the use of ketamine.28 The potential future for ket-
amine seems bright with possibility.
CONCLUSION
Ketamine is a unique opioid with NMDA receptor antag-
onist activity that can be beneficial in the setting of opioid
tolerance or opioid induced hyperalgesia. Ketamine admin-
istration has been investigated using various routes of
administration, though most commonly studied for pain
management is IV, PO, and topical. In the realm of pain
management, ketamine is postulated to improve pain related
to CRPS, certain types of malignant pain, intractable or
treatment-resistant chronic nonmalignant pain, and neu-
ropathic pain. At this time, more randomized, controlled
trials are needed to study the potential benefits of ketamine
at subanesthetic doses for pain management as well as deter-
mining the most appropriate route of administration and
dosing with standardized monitoring protocol. 
References
1. Niesters M, Martinin C, Dahan A. Ketamine for chronic pain:
risks and benefits. Br J Clin Pharmacol. 2013;77(2):357–367.
2. Ketamine. Drug Enforcement Administration. Office of Diversion
Control. Drug & Chemical Evaluation Section. Last updated 2013 Aug.
3. Pasero C. Ketamine: low doses may provide relief for some painful
conditions. Amer J Nursing. 2005;105(4):60–64.
4. Fitzgibbons EJ, Viola R. Parenteral ketamine as an analgesic adjuvant
for severe pain: development and retrospective audit of a protocol for a
palliative care unit. J Palliat Med. 2005;8(1):49–57.
5. Hirota K, Lambert DG. Ketamine: its mechanism(s) of action and
unusual clinical uses. Br J Anaesth.1996;77(4):441–444.
6. Hirota K, Lambert DG. Ketamine: new uses for an old drug?
Br J Anaesth. 2011;107(2):123–126.
7. Bredlau AL , Thakur R, Korones DN, et al. Ketamine for pain in adults
and children with cancer: as systematic review and synthesis of the litera-
ture. Pain Med. 2013;14:1505–1517.
8. National Health Service. Scotland Palliative Care Guidelines:
Ketamine. Available at: www.palliativecareguidelines.scot.nhs.uk/
guidelines/medicine-information-sheets/ketamine.aspx.
9. Connolly SB . Prager JP, Harden N. A systematic review of ketamine
for complex regional pain syndrome. Pain Med. 2015;16:943–969.
Q4  | 2016
10. Ketamine. Lexi-comp Online. Available at: online.lexi.com/lco/action/
home/switch?siteid=983.
11. Agres T. Anesthesiologists take lead as ketamine clinics proliferate.
Anesthesiology News. December 2015. Available at: www.anesthesiology-
news.com/PRN -/Article/12–15/Anesthesiologists-Take-Lead-As-
Ketamine-Clinics-Proliferate/34407/ses=ogst.
12. Bruehl S. Complex regional pain syndrome. BMJ . 2015 Jul 29;351:h2730.
13. Bruehl S, Harden RN, Galer BS, et al. External validation of IASP
diagnostic criteria for Complex Regional Pain Syndrome and proposed
research diagnostic criteria. Pain. 1999;81:147–154.
14. Harden RN, Bruehl S, Perez RSGM , et al. Validation of proposed
diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain
Syndrome. Pain. 2010;150(2):268–274.
15. Sigtermans MJ, van Hilten JJ, Bauer MCR , et al. Ketamine produces
effective and long-term pain relief in patients with Complex Regional Pain
Syndrome Type 1. Pain. 2009;145:304–311.
16. Schwartzman RJ, Alexander GM , Grothusen JR , et al. Outpatient
intravenous ketamine for the treatment of complex regional pain syndrome:
a double-blind placebo controlled study. Pain. 2009;147:107–115.
17. Noppers IM , Niesters M, Aarts LPHJ . Drug-induced liver injury follow-
ing a repeated course of ketamine treatment for chronic pain in CRPS type
1 patients: a report of 3 cases. Pain. 2011;152:2173–2178.
18. Harden RN . Ketamine analgesia: a call for better science. Pain Med.
2012;13(2):145–147.
19. National Comprehensive Cancer Network ( NCCN) Clinical Practice
Guidelines in Oncology Adult Cancer Pain Version 2.2016. Available at:
www.nccn.org/professionals/physician_gls/f_guidelines.asp#pain.
20. Salas S, Frasca M, Planchet-Barraud B, et al. Ketamine analgesic
effect by continuous intravenous infusion in refractory cancer pain:
Considerations about the clinical research in palliative care. J Palliat Med.
2012 Mar;15(3):287–293.
21. Hardy J, Quinn S, Fazekas B, et al. Randomized, double-blind,
placebo-controlled study to assess the efficacy and toxicity of
subcutaneous ketamine in the management of cancer pain. J Clin Oncol.
2012 Oct 10;30(29):3611–3617.
22. Bell RF, Eccleston C, Kalso EA . Ketamine as an adjuvant to opioids for
cancer pain. Cochrane Database Syst Rev. 2012 Nov 14;11:CD 003351.
23. Marchetti F, Coutaux A, Bellanger A, et al. Efficacy and safety of oral
ketamine for the relief of intractable chronic pain: A retrospective 5-year
study of 51 patients. Eur J Pain. 2015 Aug;19(7):984–993.
24. Hagen EM , Rekand T. Management of neuropathic pain associated
with spinal cord injury. Eur J Pain. 2015 Aug;19(7):984–993.
25. Sawynok J. Topical and peripheral ketamine as an analgesic.
Anesth Analg. 2014 Jul;119(1):170–178.
26. Johnson & Johnson, Products & Operating Company. Esketamine
receives breakthrough therapy designation from U.S. Food and Drug
Administration for major depressive disorder with imminent risk for
suicide. Available at: www.jnj.com/news/all/Esketamine-Receives-Break-
through-Therapy-Designation-from- US -Food-and-Drug-Administra-
tion-for-Major-Depressive-Disorder-with-Imminent-Risk-for-Suicide.
Published 16 August 2016.
27. News Release from Behavioral Healthcare: Insight for Executives.
Naurex initiates phase II trial of GLYX-13 antidepressant. Available at:
www.behavioral.net/news-item/naurex-initiates-phase-ii-trial-glyx-13-
antidepressant. Published 8 July 2011.
28. ClinicalTrials.gov: A service of the U.S. National Institutes of Health.
Available at: clinicaltrials.gov/ct2/results?term=ketamine&recr=Open&
no_unk=Y&pg=5.
www.painweek.org  | PWJ | 35
 Mallick-Searle ms, rn-bc, anp-bc
By Theresa 

In the United States, over 73 million surgical procedur

 The role of

Mallick-Searle ms, rn-bc, anp-bc

By Theresa 

in the acute care setting

res are performed annually, and most patients report experiencing a high
 e
ADVANC D   PRACTiCe PROViD R e

abstract: Millions of patients each year

suffer from acute pain as a result of trauma,
illness, or surgery, and pain is the most
common reason for presentation to the
emergency department.1 The prevalence
of intense acute pain is similarly high
among patients undergoing surgery: in
the United States, over 73 million surgi-
cal procedures are performed annually,
and most patients report experiencing
a high degree of pain postoperatively.2
Studies indicate that treatment of acute
pain remains suboptimal due to attitudes
and educational barriers on the part of
clinicians and patients, as well as the in-
trinsic limitations of available therapies.1
Inadequate management of acute pain
negatively impacts numerous aspects of
patient health and may increase the risk
of developing chronic pain. This article
reviews the role of the advanced practice
provider in the acute care setting, focusing
on the use of preemptive and multimodal
analgesia; imparting an understanding
of the importance of identifying patients
at risk for poor outcomes regarding pain
management in the acute care setting;
and helping educate the clinician about
tools available for improved pain man-
agement outcomes in the hospitalized
patient.

degree of pain postoperatively”

 To avoid [undermanaged pain], the advanced
practice provider who delivers primary care
to the patient in the acute setting…needs to have
a general understanding of basic pain
pathophysiology, pain pharmacology, and an
appreciation for behavioral management as
well as mind-body therapies.”

There has been much emphasis, recognition, and education

on the public health issue surrounding undermanaged chronic
pain in the United States.3 In addition, there has been much
reported about the economic impact of undermanaged
pain.4 What is less recognized or emphasized is the impact of
undermanaged pain in the acute care setting. ¶ A landmark study
of the impact of acute pain management in the hospitalized
patient over a 10-year period revealed that improvement in pain
management has not kept up with other advances in healthcare:
reports of “any pain” and “extreme pain” were reported as
higher.2 Pain continues to be a prevalent problem for medical
and surgical inpatients.5,6 Additionally, Pletcher et al found in
their research that 40% of the over 100 million emergency
department (ED) visits annually are for acute pain.7

Q4  | 2016 www.painweek.org  | PWJ | 39

ADVANCED PRACTICE PROVIDER

IN THe ACUTe CARe SeTTiNG Research shows that patients who struggle with high cat-
astrophizing, somatization, chronic pain, high opioid/
The reason for undermanaged pain in the acute care set- benzodiazepine use, poor coping, and poor social support
ting is multifactorial. To avoid it, the advanced practice are at increased risk for poor pain management when com-
provider (APP) who delivers primary care to the patient pared with their peers.8 Patients undergoing certain types
in the acute setting— OR , ICU, infusion center, medical/ of surgeries where there is a high risk of nerve damage or
surgical in-patient setting, ED —needs to have a general compromise, such as thoracotomy or amputation, are also
understanding of basic pain pathophysiology, pain phar- at increased risk for higher levels of pain postoperatively, as
macology, and an appreciation for behavioral management well as the development of chronic pain.8
as well as mind-body therapies. APPs working in trauma,
oncology, palliative care, and surgery also need to have The setting of expectations and treatment goals begins in
an awareness of regional analgesic techniques and thera- the clinic, and these goals should continue to be reviewed
pies—a basic understanding of the peripheral and central throughout the acute care treatment period. Setting expec-
nervous system is necessary. What must be avoided is pro- tations up front reduces patient anxiety9 about “not being
viders’ insufficient knowledge of pain pharmacology and heard” by the acute care team, reduces the possibility of
other treatment options, fear of medication side effects, unmanaged pain, clarifies patient’s expectations and under-
not setting expectations or discharge planning, and inad- standing about the acute care period, and gives the patient
equate initial identification of patients at increased risk for an opportunity to discuss aftercare.
poor outcomes.
Communication must begin with the first provider to iden-
Preemptively, the APP who will deliver primary care to the tify patients at risk for poor pain management outcomes,
patient planning a hospitalization or outpatient surgery, and and continue with all providers interacting with that
the APP preparing the patient for the hospital course in patient during the course of the acute care experience. Pri-
the anesthesia pre-op clinics, and the APP working as part mary communication must include discussion of current
of the surgical team or specialty medicine services (pul- medications that the patient is taking, including opioids,
monary, oncology, transplant, etc) all have a role to play in benzodiazepines, and muscle relaxants; other adjuvant
pain management. pain medications such as anticonvulsants and antidepres-
sants; and use of other substances such as cannabinoids,
Key aspects to ensuring superior outcomes at this phase ethyl alcohol, etc. Any primary mood disorders—such as
in the process include identification of patients at risk for preexisting depression, anxiety, and substance abuse dis-
poorly managed pain; patient education, including review- orders—must be recognized and discussed. Paramount
ing goals and setting expectations; and timely communica- in the communication hierarchy is the dialogue with the
tion with anticipated members of the patient’s care. anesthesia provider in using advanced therapies such as IV

40 | PWJ | www.painweek.org Q4  | 2016
 infusions with lidocaine and/or ketamine for the patient The general goals of pain management in the acute care
at increased risk for poorly managed postoperative pain.10 setting, first and foremost, include identifying the source
The use of regional anesthetic techniques should be dis- and addressing the cause of pain. Acute pain should be man-
cussed as well.11 aged aggressively and in a thoughtful manner, to expedite
discharge and, we hope, to reduce the incidence of persistent
pain. Any intervention, be it pharmaceutical or procedural,
IT’S JUST PAiN?! should aim to maintain alertness and functionality, along
with minimizing side effects. Finally, the APP should aware
Deleterious effects of unmanaged pain in the acute care of the sensory and affective component of pain, with an aim
setting can impact a multitude of systems. Complications of reducing subjective suffering.
may include:
The development of treatment protocols for pain and symp-
●●Cardiovascular: tachycardia, decreased pulmonary tom management within particular specialty groups can
vascular reserve, arrhythmias, myocardial infarction help expedite the process of treatment and reduce unnec-
for susceptible patients essary suffering. Treatment protocols/guidelines can be
helpful in many environments, including the ED.13-15 The
●●Pulmonary: splinting, atelectasis, infection intensive care unit, where the level of patient acuity and
risk of delirium are high, is also well served by pain man-
●●Gastrointestinal: reduced motility, nausea, agement guidelines.16 Additionally, outside of the critical
vomiting, ileus, obstruction setting and within the acute care hospital, pain manage-
ment protocols and guidelines can also expedite care and
●●Renal: oliguria, urinary retention reduce suffering.17

●●Coagulation abnormalities: altered platelet

aggregation, venostasis, deep vein thrombosis/
pulmonary embolus
●●Psychological impacts: increased anxiety,
fear, depression
Additionally, undermanaged pain can lead to an overall
delayed recovery, slower return to function, possible delayed
hospital discharge, and increased cost.12
DiSCHARGe PLANNiNG
Discharge planning should begin along with the plan for
admission. The APP arranging for inpatient radiation ther-
apy for the oncology patient, for example, should have a plan
for managing the patient’s increased pain posttreatment.
The APP preparing the patient for a total joint replacement
due to chronic osteoarthritis should have a plan for postsur-
gical pain management and for pain with physical therapy

Q4  | 2016 www.painweek.org  | PWJ | 41

ADVANCED PRACTICE PROVIDER

Discharge planning should begin along with

the plan for admission. The APP arranging for
inpatient radiation therapy for the oncology patient,
for example, should have a plan for managing the
patient’s increased pain posttreatment.”

as the patient rehabilitates. The APP seeing the patient in ●●If a difficult discharge is anticipated, engage
the ED or urgent care setting should help arrange for the case-management early in the admission.
patient to be seen by their primary care provider. Pain is the
most commonly reported reason for unanticipated admis- ●●Verify hospital follow up, preferably within 2 weeks
sion or readmission.18 of discharge.

Being asked to discharge a patient from an acute hospital- ●●Provide the patient with only enough discharge
ization can be challenging for an APP. He or she may not medications (including opioids) to get to their
have been involved in the day-to-day care of the patient, follow-up visit. Provide written instructions on any
especially if there has not been adequate follow up arranged; new medication’s side effects, their safe use, and
or if the patient has been started on new medications for contact information for questions.
pain during the admission (that may or may not be cov-
ered by the patient’s insurance); or if the expectation is to
provide the patient with a new opioid prescription or for a CONCLUSiONS
much higher dose than the patient may have come into the
hospital on. There should always be a good sign-out, which Millions of patients each year suffer from acute pain as a
speaks to the importance of excellent communication with result of trauma, illness, or surgery. Even with the recogni-
the provider(s) who have been managing the patient’s care tion that undertreated pain remains a public health concern,
most consistently during the admission. Hospital care-man- and that costs to the US healthcare budget are greater than
agers can assist with disposition needs, some prescription most other chronic diseases combined, the management of
insurance issues, and coordination of care. pain in the acute care setting still remains underemphasized.
The management of pain in the acute care setting is the
responsibility of all healthcare providers involved in that
PeARLS OF WiSDOM patient’s care, from the decision to hospitalize the patient,
to the acute care setting itself, and finally the aftercare that
●●Hospital discharges can be challenging on the may reduce the need for readmission. As advance practice
weekends for all the above mentioned reasons. providers continue to provide the majority of the pre- and
Aim for discharges during the week, preferably aftercare to these select patients, they are also providing an
during business hours. increasing amount of the inpatient acute care as they join
surgical specialty practices, working in anesthesia as primary
providers and in the critical care settings of ICU and ED. 

42 | PWJ | www.painweek.org Q4  | 2016
 Table. Nonopioid pain medications commonly used in the acute care setting
Drug Class Example/Typical Dosing Major Considerations Indication

Anticonvulsants »» Gabapentin—300 to 1200 mg tid Renally excreted Neuropathic pain

»» Pregabalin—50 to 150 mg tid

Antidepressants »» Duloxetine—20 to 60 mg/day Neuropathic pain/

comorbid depression
»» Desipramine—25 to 100 mg/day

Muscle relaxants »» Baclofen—5 to 10 mg tid Muscle spasm

»» Flexeril—5 to 10 mg tid

NSAIDs »» Celecoxib—100 to 200 mg qd-bid Bleeding risk, renal considerations Nociceptive pain
»» Ketorolac—10 mg oral q6h, 30 to
60 mg IV q6h

Acetaminophen n/a—1000 mg tid-qid; oral and Hepatic dosing; IV, oral, Nociceptive pain
IV dosing equivalent rectal administration

Lidocaine IV infusion—1 mg/kg/h No oral equivalent; additionally Neuropathic pain

beneficial when patient is NPO

Melatonin receptor »» Melatonin—3 to 10 mg/evening Sleep difficulty

agonists »» Ramelteon—8 mg/night

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1. Sinatra R. Causes and consequences of in adequate management of
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to be unmanaged. Anesth Analg. 2003;97:534–540.
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Care, and Education. Relieving Pain in America: A Blueprint for Trans-
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14. The American Academy of Emergency Medicine: Model
Emergency Department Pain Treatment Guidelines. Available at:
www.aaem.org/publications/news-releases/model-emergency-
department-pain-treatment-guidelines.
15. Ohio State Recommendations: Implementing Prescribing Guidelines in
the Emergency Department. Available at: www.healthy.ohio.gov/-/media/
HealthyOhio/ASSETS/Files/ED/
Implementing-Prescribing-Guidelines-in-the-Emergency-Department.
pdf?la=en.

7. Pletcher MJ, Kertesz SG, Kohn MA , et al. Trends on opioid prescribing
by race/ethnicity for patients seeking care in US emergency departments.
JAMA . 2008;299:70–78.
8. Macintyre PE, Schug SA , Scott DA , et al, APM:SE Working Group of
the Australian and New Zealand College of Anaesthetists and Faculty of
Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd ed.
ANZCA & FPM , Melbourne; 2010.
9. Powell R, Scott NW, Manyande A, et al. Psychological preparation
and postoperative outcomes for adults undergoing surgery under general
16. Hajiesmaeili MR , Safari S. Pain management in the intensive care unit:
do we need special protocols? Anesth Pain Med. 2012 Spring;1(4):237–238.
17. Society of Hospital Medicine: improving pain management implemen-
tation guide. Available at: tools.hospitalmedicine.org/resource_rooms/
imp_guides/Pain_
Management/PainMgmt_Final3.4.15.pdf
18. Coley KC , Williams BA , DaPos SV, et al. Retrospective evaluation of
unanticipated admission and readmissions after same day surgery and
associated costs. J Clin Anesth 2002;14(5):349–353.

Q4  | 2016 www.painweek.org  | PWJ | 43

 By Donna D. Alderman do
abstract: Prolotherapy is a method of regenerative injection treatment that stim-
ulates healing.1 This therapy has been in practice for decades in the treatment
of musculoskeletal pain and osteoarthritis, and has evolved to include the use
of platelet rich plasma (PRP) and autologous adult stem cell sources, such as
bone marrow and adipose (fat) stem/stromal cells. Chronic musculoskeletal
pain is the most common medical complaint in the United States, and one of
the most common reasons for primary care visits.2 The American Academy of
Orthopedic Surgeons estimates that 1 in 2 adults—126.6 million people—are
affected by a musculoskeletal condition, comparable to the total percentage of
Americans living with a chronic lung or heart condition, costing an estimated
$213 billion in annual treatment, care and lost wages.3 Osteoarthritis (OA) is
also a major health issue, and the most common joint disease, affecting millions
of people in the United States.4 Typical medical recommendations for these
conditions include prescription medications, which offer temporary relief but
may have addiction potential or other unwanted side effects; cortisone, which
sometimes helps but can have adverse effects on joints and joint tissue; hyal-
uronic acid joint injections, which are only temporary; physical therapy, osteo-
pathic or chiropractic treatments, which may help, but not in every case; and
of course surgery, which is not always indicated, has additional risk and may
fail. In May 2016 Orthopedics Today reported a high incidence of pain 1 year
after total knee replacement.5 Surgeons themselves are questioning whether
surgery is always the best answer. A 2016 journal article compared surgery
to other more conservative treatments for knee OA and concluded: “Surgery
has historically been considered the final solution for treatment of knee osteo-
arthritis,” however, “there are increasing concerns regarding the lack of ran-
domized controlled studies to support this opinion.”6 Therefore the need for
a safe and effective nonsurgical treatment for musculoskeletal pain and OA
is evident. Prolotherapy is low risk and has a high success rate. The newer,
more biologic formulas, such as PRP and stem cell sources, allow treatment of
more severe chronic as well as acute issues, while use of musculoskeletal ultra-
sound for diagnosis and injection guidance improves accuracy and precision.

44 | PWJ | www.painweek.org Q4  | 2016
 e e
COMPLEMENTARY&ALT RNATiV

Prolotherapy
has been
in existence
since the
1930s…

46 | PWJ | www.painweek.org Q4  | 2016
 rolotherapy has been in existence since the 1930s when Earl Gedney, DO, a general
surgeon at the Philadelphia College of Osteopathic Medicine, caught his thumb
in closing operating room doors, stretching and spraining it. After several
months of pain and instability in that joint, he was told to just live with it and
change professions. Dr. Gedney was not of the mindset to agree with this, so he
started researching possible options. He knew of a common practice in those
days of physician “herniologists.” These doctors treated hernias by injecting the
stretched hernia connective tissue ring with an irritating solution, promoting
closure of the defect. Dr. Gedney extrapolated his knowledge of nonsurgical
hernia repair to the nonsurgical repair of joints, ligaments, and tendons. He
concluded that ligament and tendon laxity (looseness) causes joint instability,
leading to pain, and could be resolved by strengthening the joint connective
tissue. Reasoning he had little to lose by being a guinea pig for this theory, he
started injecting his thumb with these irritating solutions and had a dramatically
successful result. Before long, he was back working as a surgeon. Excited about
his result, he started on a lifelong career of research into this technique. In June
1937 he published the first known case report and journal article about the special
technique,7 followed by a presentation at the February 1938 meeting of the
Osteopathic Clinical Society of Philadelphia called The hypermobile joint further —

reports on injection method.

A decade later another pioneer, George Hackett,
MD, coined the word “prolotherapy,” short for “proliferation
therapy,” for its ability to stimulate repair and proliferation
of new connective tissue at joint injury sites. Dr. Hackett
went on to publish the first formal textbook on the subject in
1956.8 The medical community eventually agreed that joint
instability and ligament laxity lead to pain and osteoarthritis,
and in 1972, Lancet wrote that joint instability is a leading
contributor not only to irregular biomechanics and pain, but
the subsequent development of OA .9 It is now well accepted
that there is a significant association between joint injury,
resulting joint instability, and then later OA .10 Prolotherapy
is therefore an excellent treatment for OA because it not
only addresses ligament injury and joint laxity, reducing
instability and pain,11 but may also prevent further joint
biomechanical damage and OA . Recent studies also show
that all the various forms of prolotherapy have the potential
to stimulate cartilage regeneration.12-14

Q4  | 2016 www.painweek.org  | PWJ | 47

COMPLEMENTARLY&ALTERNATIVE

Prolotherapy: the body to repair old injuries by activating a new healing

which conditions?
Prolotherapy has traditionally been used for chronic inju-
ries or pain, however it has come into use for treatment of
acute injuries to stimulate faster, stronger healing. Common
conditions treated15 are:
→→Tendinitis/tendinosis, repetitive strain injuries,
shoulder pain, rotator cuff tears
cascade, raising growth factor levels and effectiveness.17 In
a recent publication with pre- and posttesting and biopsies,
dextrose prolotherapy was also shown effective in cartilage
regeneration.12 There is a large volume of medical research
including double blinded and placebo controlled studies,
showing the effectiveness and safety of dextrose prolother-
apy, including a recently published review.18

→→Ligament sprains, other sports injuries Platelet-rich plasma prolotherapy

→→Knee pain, meniscal tears, ligament tears
→→Osteoarthritis and degenerative joint/
disc disease
→→Low back pain, sacroiliac joint pain/
instability, sciatica
→→Neck pain, whiplash, headache
→→Elbow pain, golfer’s and tennis elbow
→→Ankle and foot pain, plantar fasciitis
→→Wrist and finger pain, thumb and finger OA
→→High hamstring tendinopathy,
iliopsoas tendinopathy
PRP has been used in prolotherapy for over 10 years. Many
people have heard the term as a treatment for musculoskel-
etal and sports injuries, but do not realize it is a form of
prolotherapy. Studies support the use of PRP for tendinop-
athy,19 chronic tendon and muscle injury,20 joint degenera-
tion,21 and OA , including a study showing PRP to be more
effective than hyaluronic acid for knee22 and hip OA .23 It
is believed that PRP can also modulate action on articular
cartilage lubrication and regeneration.13 There is a huge
interest by orthopedic medicine physicians in PRP, with
many, many journal publications and studies, as well as a
recent textbook on its use in musculoskeletal medicine.24
There are also some interesting observations, including a
case report of calcific tendonitis in a rotator cuff, treated
with PRP. Results showed not only excellent resolution of
symptoms and pain, but also X-ray evidence that calcium
deposits previously present in the tendon were gone when
followed up 1 year later.25

→→Hip pain, iliotibial band syndrome, hip OA Biocellular (stem cell) prolotherapy
(as long as it’s not end stage) Biocellular (stem cell or stem/stromal cell) prolotherapy
is so named because it uses adult stem cell sources as the
→→Temporomandibular joint dysfunction prolotherapy treatment formula. Biocellular prolotherapy
is used when a more aggressive healing process is needed
→→Hypermobility or desired. In the early 1990s, adult stem cells, specifically
mesenchymal stem cells (MSCs), were discovered to have
→→Other musculoskeletal pain an active role in connective tissue repair after injury.26,27
MSCs are partially differentiated cells capable of continuing
down the lineage to ligament, tendon, or cartilage cells.28
Types of It is also believed that these cells work by changing the
prolotherapy tissue and joint microenvironment more favorably towards
There are 3 general formula types in prolotherapy: tradi- healing.29 [See Figure 1 at goo.gl/guojfB.] An individual is
tional (dextrose), platelet-rich plasma ( PRP) and biocellular, born with these adult stem cells, they are found throughout
also known as stem cell prolotherapy, which uses autologous the body, multiply to replenish dying cells and regenerate
stem cell sources, ie, typically bone marrow or adipose (fat) damaged tissues. The 2 main storage reservoirs of MSCs in
stromal tissue. the human body are bone marrow and adipose (fat) tissue,
and both of these can be used as stem cell sources in pro-
lotherapy. Adipose is an interesting tissue because it con-
Traditional prolotherapy tains 500 to 2000 times as many MSCs as bone marrow.
Traditional, also referred to as dextrose prolotherapy, uses Adipose also retains its regenerative abilities much longer
hypertonic (10% to 15%) dextrose as its main proliferating as a person ages than bone marrow does,30 as well as being
formula. Hypertonic dextrose creates an osmotic irritation easier to harvest, making adipose an ideal stem cell source,
which then promotes positive inflammation and healing.16 especially for older patients.31,32 The first protocol for adi-
At its core, this treatment could be thought of as “tricking” pose derived biocellular prolotherapy was published in 2011

48 | PWJ | www.painweek.org Q4  | 2016
 in Journal of Prolotherapy.33 Another advantage of adipose, or PRP, and in other cases biocellular (stem/stromal cell) is
observed specifically when treating knees, is its potential the most practical starting point, depending on the patient’s
to replenish the knee infrapatellar fat pad. This fat pad not presentation and injuries. Patient preference is also import-
only provides a cushion, but also contains potent MSCs and ant as the doctor-patient relationship is a partnership, and,
MSC precursors.34 It has been speculated that depletion of once the patient understands the process, his/her input is
this fat pad plays a prominent role in the initiation and pro- important in this determination. Each patient is evaluated
gression of OA in the knee.35 Many cases of adipose derived individually, and recovery may be faster in some cases than
biocellular prolotherapy have been done in the knee since others. An average number of traditional or PRP prolother-
2011 and show objective ultrasound evidence demonstrat- apy treatments is 4 to 6, spaced 4 to 6 weeks apart. An aver-
ing infrapatellar fat pad improvement that correlates with age number of treatments for biocellular prolotherapy is
reduction of patients’ pain and improved function. Biocel- 1 to 2, spaced 6 to 9 months apart. In some cases a patient
lular prolotherapy has also been used successfully in cases may start with one form of prolotherapy, and then advance
of tendon injury and for acute sports injuries where faster to a more aggressive form if results level off. See the treat-
healing is desired along with the possibility of reduced scar ment course algorithm (Figure) of where to start, when to
tissue formation. [See Figures 2, 3, and 4 at goo.gl/guojfB.] switch, and how long the process typically takes.

Who is an appropriate patient Use of diagnostic

for prolotherapy?
In the Hackett prolotherapy text book, first published in
1956 with 4 subsequent editions, the question of who was
appropriate as a candidate for prolotherapy treatment was
addressed.36 This book states that a patient should have:
1 An appropriate medical problem
2 A desire for improvement
3 No underlying medical condition that would
significantly interfere with healing
4 A willingness to report progress
5 A willingness to receive painful injections in an
effort to recover from injury
These criteria are still true today. It is important for the
patient to understand this is a process of healing, and that
the treated area is being stimulated to heal so will often
feel worse initially before it feels better. There is also an
“ebb and flow”—a “4 steps forward, 2 steps back” phenom-
ena—which occurs during the interval after treatment.
This is especially true with PRP or biocellular prolother-
apy because these are more aggressive formulas, stimulate
deeper healing, and are often more uncomfortable than dex-
trose prolotherapy. The most important common denom-
inator between patients who are successful is patience and
an understanding of the treatment process.
When to use which type
of prolotherapy and
how long does it take?
As a physician doing prolotherapy for 20 years, it is my
practice to start with the least aggressive formula that I
believe will get the job done. In some cases that is dextrose
musculoskeletal ultrasound
Ultrasound as a tool in diagnosis and treatment for muscu-
loskeletal medicine has been gaining popularity in recent
years.37 The ability to immediately correlate the exact spot
where a patient is having pain to an image can result in a
faster and better diagnosis. While MRI has its place, ultra-
sound may show more detail than MRI for certain locations,
multiple joints can easily (and inexpensively) be scanned
including contralateral joints, and every patient can get an
ultrasound, even those with metal implants.38 Dynamic
(movement) imaging can also be accomplished, to correctly
estimate the extent of damage of a ligament or tendon tear.
MRI falls short here as scans are done with the patient
motionless, and some connective tissue tears do not show
up unless the joint is mobilized.39 The use of ultrasound can
also be valuable as a “GPS” while injecting difficult locations.
And serial ultrasounds over a treatment course can help to
show progress and build patient confidence. Musculoskeletal
ultrasound is fast becoming the standard of care in physical
medicine and rehabilitation physician training programs.40
Better machines are being produced, and just like when
computers came down in size and price, very sophisticated,
high quality ultrasound machines are now available that
are portable and affordable. Some have high end features,
such as color tissue elastography (also called sonoelastogra-
phy), which measure the stiffness or softness of tissue. This
feature, previously only available on expensive ultrasound
machines, is now being offered on smaller, more portable
devices, such as the Konica Minolta Sonimage HS1 system.
Tissue elastography, which has been used for years in other
applications, is new to musculoskeletal medicine. This tech-
nology can potentially allow the practitioner to determine
tears that were undetectable with standard black and white
imaging, where a diagnosis would otherwise not be possible.
[See Figure 5 at goo.gl/guojfB.] While there is a learning
curve in beginning to use ultrasound, it is well worth the
effort as any tool which can help the pain practitioner better
diagnose and resolve a patient’s pain origin is invaluable.

Q4  | 2016 www.painweek.org  | PWJ | 49

COMPLEMENTARLY&ALTERNATIVE

Figure. Typical prolotherapy treatment algorithm.

Treatment algorithim

Evaluation:
patient history, physical exam,
review of previous studies,
musculoskeletal ultrasound in
office to confirm diagnosis

Determine if candidate for

dextrose, PRP, or
stem cell prolotherapy

Discuss options

If excess degeneration, If average case

severe tendonosis,
muscle tear,
or if patient Dextrose prolotherapy
prefers PRP over × 2 treatments, interval 3–4 weeks
dextrose prolotherapy,
and if no
contraindications Re-evaluate

PRP prolotherapy
× 2 treatments, If no substantial If doing well,
interval 4–6 weeks improvement or continue treatment
if results
have plateaued
Dextrose prolotherapy
Re-evaluate × 2–4 treatments,
interval 3–4 weeks

If doing well, If no substantial Should be completed and

continue re-evaluating improvement or 90% – 100% improved.
every treatment if results If not, re-evaluate,
have plateaued consider PRP prolotherapy
or biocellular (stem cell)
Usual course prolotherapy
4–6 treatments Biocellular (stem cell) prolotherapy
should be completed and (note: may also start here as
90% – 100% improved* indicated by severity
of problem or patient preference)
× 1–2 treatments,
6–12 months apart

PRP prolotherapy
if needed at recheck visits *Based on a combination of
× 1–2 treatments objective and subjective measures,
such as pain reduction, better
stability, increased function, and
Should be completed and improved on orthopedic testing and
ultrasound imaging.
90% – 100% improved*

50 | PWJ | www.painweek.org Q4  | 2016
 [Prolotherapy] could be
thought of as ‘tricking’
the body to repair
old injuries by activating a
new healing cascade,
raising growth factor levels
and effectiveness.
Conclusion
Musculoskeletal pain and osteoarthritis are common com-
plaints and can be a challenge for the treating physician.
Traditional medical treatment options may not be straight-
forward, and may be only temporary, ineffective, or high
risk. Osteoarthritis has been shown to develop after con-
nective tissue injury, which leads to biomechanical change
and ultimately degeneration and pain. Traditional dextrose
prolotherapy, PRP prolotherapy, and biocellular (stem cell
or stem/stromal cell) prolotherapy are low risk procedures
with a high success rate. These procedures are regenerative
in nature and work by stimulating repair of joints, ligaments,
tendons, muscle and cartilage. An added benefit is that when
joints are stabilized, biomechanical joint injury and fur-
ther OA may be prevented. Different types of prolotherapy
are appropriate for different situations and conditions, and
the choice of which form of prolotherapy to use is arrived
at after a thorough evaluation, diagnostic musculoskele-
tal ultrasound and/or other imaging, discussion with the
patient, and a working diagnosis as to what is causing his/
her pain. While prolotherapy regenerative medicine is the
wave of the future, now encompassing platelet and stem cell
biotechnology, its origins are from the past and based on a
very simple premise that the body can be stimulated to heal,
reducing or eliminating pain. 
Q4  | 2016
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10. Blalock D, Miller A, Tilley M, et al. Joint instability and osteoarthritis.
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13. Sakata R, Reddi AH . Platelet-rich plasma modulates actions on
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14. Pak J, Lee JH, Kartolo WA , et al. Cartilage regeneration in human
with adipose tissue-derived stem cells: current status in clinical implica-
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15. Alderman DD. Regenerative injection therapies for pain: traditional,
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Sukiennik AW, eds. Integrative Pain Management. In: Oxford, England:
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16. Brody JE . Injections to kick-start tissue repair. NY Times. 2007:D8.
17. Reeves KD. Normal tendon and ligament healing. In: Lennard T. Pain
Procedures in Clinical Practice. Philadelphia, PA: Hanley & Belfus; 2000:172.
18. Hauser RA , Lackner JB, Steilen-Matias D, et al. A systematic review of
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19. Fitzpatrick J, Bulsara M, Zheng MH . The effectiveness of platelet-rich
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20. Mishra A, Woodall J, Vieira A. Treatment of tendon and muscle using
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31. Frese L, Dijkman PE, Hoerstrup SP. Adipose tissue-derived stem cells in
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32. Alderman DD. Advances in regenerative medicine: high-density
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21. Filardo G, Kon E, Roffi A, et al. Platelet-rich plasma: why intra-

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22. Laudy AB, Bakker EW, Rekers M, et al. Efficacy of platelet-rich plasma
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23. Dallari D, Stagni C, Rani N, et al. Ultrasound-guided injection of

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24. Maffulli N. Platelet Rich Plasma in Musculoskeletal Practice. Springer-

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25. Seijas R, Ares O, Alvarez P, et al. Platelet-rich plasma for calcific

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26. DiMarino AM , Caplan AI, Bonfield TL . Mesenchymal stem cells in

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27. Hiroshi M. Adipose-derived stem cells for tissue repair and regener-
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52 | PWJ | www.painweek.org Q4  | 2016
SHORT CUTS

By Doug Gourlay MD, MSc, FRCPC, FASAM

The diagnosis of addiction

is made prospectively,
over time.
The diagnosis of pseudoaddiction
is made retrospectively.

Substance misuse is a primary care issue.

Primary care practitioners need to
play a key role in “demand reduction”
whether it’s patient use of
nicotine, alcohol, or cocaine.
Through your longitudinal role
with the patient, the true nature of
an occult substance use disorder
will become apparent.
Primary care also has the ability
to see the patient in a more complete sense,
often through multiple situations
and multiple sets of eyes—
how a patient responds to your
administrative staff; input from the
pharmacist; and, where possible,
input from the patient’s significant other—
can all offer insight that a
consultant may never have.

Q4  | 2015 www.painweek.org  | PWJ | 53

SHORT CUTS
1 | Pain Practice—The
Changing Landscape
for Primary Care
Jennifer Bolen, JD
Practitioners need a system
to ensure that they’re actively
current on licensing board
requirements and clinical
guidelines relating to the long-
term use of opioid therapy. SAMHSA has a kit for prescribers, patients and
family members, that relates to opioid overdose issues, and will help the
provider fulfill the informed consent requirement when opioids are pre-
scribed. It’s also useful information to use to train staff. And if there’s ever
an investigation and a need to engage an attorney, this little handbook of
clinical material could be a good reference resource. Most importantly, the
amount of education that a provider can give to a patient on these issues
is super critical. By educating the patient, you are putting them on notice
that they do have responsibilities—safe use, safe storage, safe disposal
of the medicine; asking questions; being engaged; and talking about
any possible adverse events. Patient breathing problems might trigger a
provider to say, “Hey, let me help you with this additional medicine, just in
case something goes wrong. I’m not labeling you an abuser or an addict.
I simply want to care for you and give you a tool, like an epinephrine pen
you would have if you were an asthmatic, in case you feel like you might be
having an overdose event.” That education, that sharing in responsibility,
and that recognition of patient responsibility is critical. Providers who do
that are really taking steps in good faith to help protect their patients.
4 |
2 | Pain Management in Workers Compensation
Matthew Foster, PharmD
Workers’ compensation ( WC) patients differ from the average group
health claim: most have some kind of a physical injury that led to a
chronic pain condition. In group health claims for pain therapy it’s much
more focused on management of diseases of either lifestyle or aging,
such as diabetes or hypertension. Within the WC system, there are
specific treatment guidelines at the national level and also some at the
state level that help drive towards the appropriate care of the injured
worker. They are similar in some aspects, such as identifying the typical
medications to be used to treat the injured worker, but they guide on
what is inappropriate therapy as well, so that the physicians know which
should be avoided—not only having an authorization process in place
but to point out how dangerous a medication can be when used in com-
bination with opioids. One interesting trend in WC is the push towards
implementation, such as through the adoption of state-based WC for-
mularies. There is an emphasis on identifying medications that would
be considered first-line therapy vs those that are less safe, maybe less
effective, and definitely more expensive, and using those as the second-
or third-line therapy. And an approval or review process before moving
on to the second-line therapy drugs, which would also include long-acting
opioids. Whenever a patient is injured, there are appropriate treatment
guidelines that we’re using in the WC market. But these also apply to
patients outside of Workers’ Comp. Whether you’ve sprained your back
putting up Christmas lights or because you work for a company that
installs Christmas lights, each should be treated in a safe and effective
54 | PWJ | www.painweek.org
manner using first-line medications and
trying to use those therapies that are
going to avoid long-term complications.
3 | Assessing Risk
Assessment
Ted Jones, PhD, CPE
Although most prescribers accept that
risk assessment is important, many
don’t know a lot about the tools, such as the ORT or SOAPP/SOAPP-R.
The ORT is given in paper form to the patient, and it misses a lot of
risk: one reason is abusers may lie, plus it’s hard to read and interpre-
tation becomes an issue. SOAPP-R has cut-off points, and you need to
understand which cut-off level you’re using and why, and what the pros
and cons are. Identifying risk is more than just identifying potential
addicts. Risk comes from a lot of different factors. People overtake
medicine. They have impulse control issues. They’re not sleeping. They
don’t understand. There’s literacy issues. There’s all kinds of reasons why
people cannot take their medicine as prescribed. I actually think one of
the questions that we don’t ask soon or often enough is, “Where do you
keep your medicine and has it ever gone missing? Have you ever lost
any or had it stolen?” Diversion is a huge issue and few of the risk tools
currently ask that question, so practitioners need to. If you can approach
risk in a more multidimensional fashion and address what’s driving the
risk, you’re going to be a lot more effective in your treatment outcomes.
Alcohol Misuse and Chronic Pain
Michael Weaver, MD, FASAM
Alcohol use disorder can be responsible for development of chronic pain
syndromes, due to traumatic accidents or the effect of years of alcohol
use on the body leading to peripheral neuropathies, pancreatitis, and
other chronic, painful conditions. It can make it much more challenging to
manage any kind of pain medication, whether it’s a controlled substance,
opioids, benzodiazepines, or others. All of these are challenging when
paired with alcohol. It’s useful to think of alcohol as a drug in addition
to the drugs prescribed. Initiate the conversation about using alcohol:
it should be a question that every practitioner asks. Just bringing the
problem to the attention of the patient and letting them know you have
concerns is often enough. If a practitioner just says, “I’m concerned about
this and I really think you should start to make a change” then lots of
patients will start to make a change. What we’re trying to do is increase
the patient’s motivation to change a behavior, instead of forcing them
or trying to convince them to do something. What will help that person
be more motivated to change a behavior? Motivational interviewing
is more about the approach, the style, the laid back version of trying
to get someone to change their mind or behavior and do something
healthier instead of less healthy. If that’s a problem, you don’t always
have to address it yourself at the primary care level. If alcohol use is
leading to some dangerous behaviors or even legal consequences those
are triggers to go ahead and refer to a specialist. But a PCP can still be
the bridge in order to continue the motivation and make sure that the
patient maintains their gains once they come back from specialty care.
It’s worthwhile to address alcohol use in practice. Alcohol use disorders
are treatable and treatment works.
Q4  | 2016
SHORT CUTS

A study of polyneuropathy incidence Anterior cruciate ligament (ACL) The placebo effect may be
examined injury affects some stronger than previously thought.

102 250,000 97
patients
obese individuals Americans
with chronic low back pain were
and randomized into
each year, most of whom are in
53 their 20s and 30s. 2groups,
About 1 of which received standard
lean controls.
treatment (NSAID medications)
Polyneuropathy rates were

3.8% 50%
of these require reconstructive surgery,
and the other received standard
treatment + medication clearly
labeled placebo pills.
in the controls,
3
11.1%
of whom up to After weeks,
the placebo group reported
in the obese with normoglycemia,
60% 30%
29% develop osteoarthritis (OA) within
less

5 years
in the obese with prediabetes, and typical and maximum pain,

34%
in obese patients with diabetes. of their procedure.
compared to

The research demonstrates that obesity alone
is a significant contributor to
polyneuropathy risk, even in the
absence of comorbid diabetes.1
9% 16% and
A new study will investigate these anomalies respective reductions
in patients at 3-, 6-, and 12-months reported by the first group.5
postsurgery, with the objective of
developing treatment paths to prevent A study of
OA development in this population.3

According to national statistics,

naloxone availability is
79
patients
Inflammatory bowel
who had surgery for dental
associated with a disease (IBD) includes conditions

43%
impaction found that
such as Crohn’s disease and
ulcerative colitis, and affects some
94%
drop in
opioid overdose fatalities.
1.4
million Americans.
were given opioids for their pain,
but most of the cohort took
only ½ of their
Birmingham, Alabama, and nearby
counties have seen these deaths IBD increases the risk of intestinal cancer by up prescription, leaving over
escalate from
12 in 2010 to 137 60%. 1000
doses unused.
reported in 2014. Among patients with Crohn’s disease,
But a crowdfunded study By introducing an incentivized text
that raised

$11,500
70% messaging system to some of these
patients, the researchers reported a

to purchase and distribute

naloxone kits to family and friends
eventually have surgery.
Research has not only identified a potentially
useful biomarker of IBD severity, but has also
22%
increase
of at-risk opioid users isolated a key protein, called EZH2 in proper medication disposal,
reports saving 9 such individuals that may be a new therapeutic target for compared to a control group who
from overdose death.2 IBD treatments.4 did not get the incentive.6

1. bit.ly/2eXmRLv  2. bit.ly/2fyHHPo  3. bit.ly/2fqYBSt  4. bit.ly/2fS2GxM  5. bit.ly/2fRoawz  6. bit.ly/2f8TfIM

Q4  | 2016 www.painweek.org  | PWJ | 55

SHORT CUTS

with
Paul J.
Christo
MD, MBA

Paul Christo is the

host of the Aches and
Gains radio talk show,
and an Associate
Professor at Johns
Hopkins University
School of Medicine in
Baltimore, Maryland.

56 | PWJ | www.painweek.org Q4  | 2016
 “There are many ways that we can
touch the lives of others,
and I was fortunate to have found
medicine as the way I could
best do that.”
What inspired you to become a healthcare
provider?
I first thought about becoming a physician in
high school and college, but the desire was solidified
in medical school. Medicine allowed me to make
a big impact on human lives, and to help restore
patients to a healthy and active state of living. There
are many ways that we can touch the lives of others,
and I was fortunate to have found medicine as the
way I could best do that.
In medical school, I was inspired by rotations in
anesthesiology and pain medicine. I was intrigued by
the array of analgesics available to reduce surgical
pain such as anesthetic gases, IV opioids, epidurals,
and regional nerve blocks. Then in residency training,
I saw firsthand how pain specialists used medications
and specialty procedures like nerve blocks, epidurals,
and implantations to reduce pain and suffering. I
knew at that time that I wanted to subspecialize in
pain medicine in order to make a substantial impact
on the lives of those in pain.
Why did you focus on pain management?
As an intern, I saw many patients with
inadequately controlled pain—arthritis, low back
pain, headache, and neck pain—yet I didn’t have the
Q4  | 2016
knowledge to make them better. Patient visits
were quick and most of my attendings avoided
any discussion of pain care. I could see the need
and wanted to help meet it, realizing that those
in pain were completely disenfranchised and
often hopeless.
My life’s work has focused on improving the lives of
patients in pain through clinical care, education,
and research. That drive has evolved into the creation
of a national talk show on overcoming pain called
Aches and Gains, which airs on Sirius XM radio. The
show provides a media platform for hearing the
stories of patients who have found relief, shares
cutting edge treatments from contributing experts,
and offers ways that people in pain can cope
themselves. It’s been gratifying to hear that the show
is making a meaningful impact on those in need.
Who were your mentors?
In middle school and high school, my scoutmaster
in the Boy Scouts. He was a cardiologist and led me to
the field of medicine. In college, Dr. Jeremiah Freeman
(organic chemistry), and in medical school, Dr. Mike
Heine (anesthesiologist). In residency, Drs. Sal Abdi
(pain specialist) and Bobbie Sweitzer (anesthesiologist).
Mark Hubbard (entrepreneur) has been a terrific media
and business mentor.
www.painweek.org  | PWJ | 57
PUNDIT PROFILE/PAUL CHRISTO
“I knew…that I wanted to
subspecialize in pain medicine
in order to make a
substantial impact on the lives
of those in pain.”
If you weren’t a healthcare provider, what
would you be?
I was passionate about playing the pipe organ
in high school after years of studying the piano.
I also realized that I didn’t have the talent to make a
living as a musician, so let that vision go. Instead, I
would have liked to become a CEO of a healthcare
company that delivers innovative products for treating
chronic diseases.
What is your most marked characteristic?
My persistence has been the driving factor in all
of my pursuits. I rarely give up, despite the barriers, and
try to find alternative methods of achieving the goal.
What do you consider your greatest
achievement?
My greatest accomplishment has been a
loving marriage, and raising two children.
Professionally, it’s the development of my radio talk
show, Aches and Gains.
What is your favorite language?
The language of music…
58 | PWJ | www.painweek.org
If you had to choose one book, one film,
and one piece of music to take into space for
an undetermined amount of time, what would
they be?
Book: The Magic of Believing by Claude M. Bristol.
Movie: The Pink Panther series
Music: What a Fool Believes by the Doobie Brothers
What would you like your legacy to be?
Hope is a vital part of overcoming pain. There
is no question that therapies can ease pain, but the
belief that you can feel better is even more import-
ant. You must believe that things can get better, and
remember that your life and well-being are worth the
fight. I hope that I’m remembered for responding to
human need personally and compassionately as a
visible advocate for pain care.
What is your motto?
“No one is immune to pain, but together we can
overcome it.”
Q4  | 2016
GRALISE® (gabapentin) tablets Table 2: Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in
Rx Only Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all
BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION GRALISE-Treated Patients and More Frequent Than in the Placebo Group)
This does not include all the information needed to use GRALISE safely and effectively. See full Body System – Preferred Term GRALISE Placebo
Prescribing Information for GRALISE. N = 359 N = 364
INDICATIONS AND USAGE % %
• GRALISE is indicated for the management of postherpetic neuralgia. Ear and Labyrinth Disorders
Vertigo 1.4 0.5
• GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic Gastrointestinal Disorders
profiles that affect the frequency of administration. Diarrhea 3.3 2.7
DOSAGE AND ADMINISTRATION Dry mouth 2.8 1.4
• GRALISE should be titrated to an 1800 mg dose taken orally, once-daily, with the evening meal. Constipation 1.4 0.3
GRALISE tablets should be swallowed whole. Do not crush, split, or chew the tablets. For Dyspepsia 1.4 0.8
recommended titration schedule, see DOSAGE AND ADMINISTRATION in full General Disorders
Prescribing Information. Peripheral edema 3.9 0.3
Pain 1.1 0.5
• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should
Infections and Infestations
be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Nasopharyngitis 2.5 2.2
• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should Urinary tract infection 1.7 0.5
not be used in patients with CrCl less than 30 mL/min or in patients on hemodialysis. Investigations
Weight increased 1.9 0.5
CONTRAINDICATIONS
GRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients. Musculoskeletal and
Connective Tissue Disorders
WARNINGS AND PRECAUTIONS Pain in extremity 1.9 0.5
GRALISE is not interchangeable with other gabapentin products because of differing Back pain 1.7 1.1
pharmacokinetic profiles that affect the frequency of administration. Nervous System Disorders
Dizziness 10.9 2.2
The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Somnolence 4.5 2.7
Suicidal Behavior and Ideation Headache 4.2 4.1
Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of Lethargy 1.1 0.3
suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any The following adverse reactions with an uncertain relationship to GRALISE were reported during
AED for any indication should be monitored for the emergence or worsening of depression, suicidal the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of
thoughts or behavior, and/or any unusual changes in mood or behavior. patients but equally or more frequently in the GRALISE-treated patients than in the placebo group
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after included blood pressure increase, confusional state, gastroenteritis, viral herpes zoster,
starting drug treatment with AEDs and persisted for the duration of treatment assessed. hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal
Table 1: Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in allergy, and upper respiratory infection.
GRALISE) in the Pooled Analysis Postmarketing and Other Experience with Other Formulations of Gabapentin
Relative Risk: Risk
In addition to the adverse experiences reported during clinical testing of gabapentin, the following
Incidence of Difference: adverse experiences have been reported in patients receiving other formulations of marketed
Placebo Events in Drug Additional gabapentin. These adverse experiences have not been listed above and data are insufficient to
Patients with Drug Patients Patients/Incidence Drug Patients support an estimate of their incidence or to establish causation. The listing is alphabetized:
Events Per with Events Per in Placebo with Events Per angioedema, blood glucose fluctuation, breast enlargement, elevated creatine kinase, elevated
Indication 1000 Patients 1000 Patients Patients 1000 Patients liver function tests, erythema multiforme, fever, hyponatremia, jaundice, movement disorder,
Epilepsy 1.0 3.4 3.5 2.4 Stevens-Johnson syndrome.
Psychiatric 5.7 8.5 1.5 2.9 Adverse events following the abrupt discontinuation of gabapentin immediate release have
Other 1.0 1.8 1.9 0.9
2.4 4.3 1.8 1.9
also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain,
Total
and sweating.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical DRUG INTERACTIONS
trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy In vitro studies were conducted to investigate the potential of gabapentin to inhibit the major
and psychiatric indications. cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and
Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with CYP3A4) that mediate drug and xenobiotic metabolism using isoform selective marker substrates
the risk of untreated illness. Epilepsy and many other illnesses for which products containing active and human liver microsomal preparations. Only at the highest concentration tested (171 mcg/mL;
components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed, 1mM) was a slight degree of inhibition (14% to 30%) of isoform CYP2A6 observed. No inhibition of
are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and any of the other isoforms tested was observed at gabapentin concentrations up to 171 mcg/mL
behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to (approximately 15 times the Cmax at 3600 mg/day).
consider whether the emergence of these symptoms in any given patient may be related to the illness Hydrocodone
being treated. Coadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone
Patients, their caregivers, and families should be informed that GRALISE contains gabapentin, which is (10 mg) reduced hydrocodone Cmax by 3% and 21%, respectively, and AUC by 4% and 22%,
also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were
should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of increased by 14%; the magnitude of the interaction at other doses is not known.
depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, Antacid (containing aluminum hydroxide and magnesium hydroxide)
behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability
healthcare providers. of gabapentin immediate release by approximately 20%, but by only 5% when gabapentin
Withdrawal of Gabapentin immediate release was taken 2 hours after the antacid. It is recommended that GRALISE be
Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually taken at least 2 hours following the antacid (containing aluminum hydroxide and magnesium
over a minimum of 1 week or longer (at the discretion of the prescriber). hydroxide) administration.
Tumorigenic Potential Drug/Laboratory Test Interactions
In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of False positive readings were reported with the Ames-N-Multistix SG® dipstick test for urine protein
pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance when gabapentin was added to other antiepileptic drugs; therefore, the more specific sulfosalicylic
of this finding is unknown. acid precipitation procedure is recommended to determine the presence of urine protein.
In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients USE IN SPECIFIC POPULATIONS
over 12 years of age, new tumors were reported in 10 patients, and pre-existing tumors worsened in 11 Pregnancy Category C: GRALISE should be used during pregnancy or in women who are
patients, during or within 2 years after discontinuing the drug. However, no similar patient population nursing only if the benefits clearly outweigh the risks. See full Prescribing Information for more
untreated with gabapentin was available to provide background tumor incidence and recurrence information about use of GRALISE in pregnancy.
information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors Pediatric Use
in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity less than 18 years of age has not been studied.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Geriatric Use
Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of The total number of patients treated with GRALISE in controlled clinical trials in patients with
these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and
with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as incidence of adverse events were similar across age groups except for peripheral edema, which
hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an tended to increase in incidence with age.
acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression,
other organ systems not noted here may be involved. Renal Impairment
GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in
It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, patients with impaired renal function. GRALISE should not be administered in patients with CrCl
may be present even though rash is not evident. If such signs or symptoms are present, the patient between 15 and 30 or in patients undergoing hemodialysis. [see Dosage and Administration in full
should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the Prescribing Information].
signs or symptoms cannot be established.
DRUG ABUSE AND DEPENDENCE
Laboratory Tests The abuse and dependence potential of GRALISE has not been evaluated in human studies.
Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary
for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not OVERDOSAGE
been established. Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been
reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were
ADVERSE REACTIONS observed. All patients recovered with supportive care.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in
in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients
and may not reflect the rates observed in practice. with significant renal impairment.
In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE
and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions.
In the GRALISE treatment group, the most common reason for discontinuation due to adverse
reactions was dizziness.

© March 2016, Depomed Inc. All rights reserved. APL-GRA-0298 Printed in U.S.A.
 ONCE
daily with
EVENING

Bring 24-hour relief into their routine MEAL

GRALISE is the only once-a-day gabapentinoid ONCE daily with

EVENING
ONCE daily with
EVENING
thatoffersNighttoDaycontrolofPHNpain1 MEAL MEAL

ONCE daily with

•PatientsreceivingGRALISEexperiencedsignificantpainreductionvsplacebobeginningWeek1andcontinuing
EVENING
MEAL
throughoutthe10-weekstudy(P<0.05)2,3
•AveragedailypainscorereductionforGRALISEwas-2.1vs-1.6withplacebo(P=0.013)2
Study Design:Patientsfrom89investigativesitesparticipatedinthisrandomized,double-blind,paralleldesign,placebo-controlled,multicenterclinicaltrial.Thestudyperiod
includeda1-weekbaselineperiod,followedbyrandomizationanda2-weektitrationtoaonce-dailydoseof1800mgG-GRormatchedplacebo,followedbyan8-week
maintenance-doseperiod,followedbya1-weekdose-taperingperiod.452patientswererandomized,with221receiving1800mgofGRALISEand231receivingplacebo.2
Primary endpoint:changeinthebaselineobservationcarriedforward(BOCF)averagedailypainscorefromthebaselineweektoWeek10oftheefficacytreatmentperiod.2

Learn more today at www.Gralise.com

INDICATIONS AND USAGE
GRALISEisindicatedforthemanagementofpostherpeticneuralgia(PHN).GRALISEisnotinterchangeablewithother
gabapentinproductsbecauseofdifferingpharmacokineticprofilesthataffectthefrequencyofadministration.
IMPORTANT SAFETY INFORMATION
ADVERSE REACTIONS
Themostcommonsideeffectsweredizziness(10.9%)andsomnolence(4.5%).
USE IN SPECIFIC POPULATIONS
ReductionsinGRALISEdoseshouldbemadeinpatientswithage-relatedcompromisedrenalfunction.
WARNINGS AND PRECAUTIONS
Suicidal Behavior and Ideation
Antiepilepticdrugs(AEDs)includinggabapentin,theactiveingredientinGRALISE,increasetheriskofsuicidalthoughtsor
behaviorinpatientstakingthesedrugsforanyindication.PatientstreatedwithanyAEDforanyindicationshouldbemonitored
fortheemergenceorworseningofdepression,suicidalthoughtsorbehavior,and/oranyunusualchangesinmoodorbehavior.
For more information about GRALISE, please see Brief Summary on the following page.
References: 1.GRALISE[prescribinginformation].Newark,CA:DepomedInc.;December2012.
2.SangCN,SathyanarayanaR,SweeneyM.Gastroretentivegabapentin(G-GR)formulation
reducesintensityofpainassociatedwithpostherpeticneuralgia(PHN).ClinJPain.2013;29:281-288.
3. ArgoffCE,ChenC,CowlesVE.Clinicaldevelopmentofaonce-dailygastroretentiveformulationof
gabapentinfortreatmentofpostherpeticneuralgia:anoverview.ExpertOpinDrugDeliv.2012;9:1147-1160.

© March 2016, Depomed Inc. All rights reserved. APL-GRA-0295 Printed in U.S.A. Relief Uninterrupted