PAIN
Opioids in the
management of persistent
non-cancer pain
Laura Thomson
Kiran Rait
Lucy Miller
Abstract
Persistent non-cancer pain (PNCP) is a chronic disabling condition
with a high prevalence within Europe (20%) and associated economic
burden. In recent years there has been a considerable increase in the
prescription of long-term opioids for PNCP. However, many patients
still report dissatisfaction with their treatment and the associated
disability of PNCP remains high. Opioid related adverse effects, opioid
misuse and associated morbidity and mortality remain an issue. This
article reviews the evidence for the effectiveness of long-term opioids
in the management of PNCP, the current guidelines and the associ-
ated adverse affects.
Keywords Adverse effects; chronic non-cancer pain; equivalent
doses; long-term effectiveness; modified release opioids; opioids
Royal College of Anaesthetists CPD Matrix: 2E03
The use of opioids in the management of persistent non-
cancer pain
Chronic pain is defined as pain lasting longer than 12 weeks, i.e.
beyond the accepted time for tissue to repair following trauma or
surgery. The aetiology of persistent non-cancer pain (PNCP) is
complex and is not completely understood. It is thought to be
influenced by the degree of tissue injury, emotion, personal
experience and reflection. In Europe, its estimated prevalence in
20% of adults indicates a significant health issue which impacts
on health service utilization. Despite this, only 5% of pain suf-
ferers are managed by pain specialists.1 This disabling condition
presents a considerable economic burden and has a multifaceted
impact on the patient’s quality of life e daily activities, social
experience, ability to work and mental health.
In recent years there has been a significant increase in opioid
prescription dosing, duration and frequency for chronic pain,
which is associated with a substantial cost to the healthcare
Laura Thomson BSc MB ChB is a Core Trainee in Anaesthesia at North
Devon District Hospital, UK. Conflicts of interest: none declared.
Kiran Rait BSc MB ChB is a Core Trainee in Anaesthesia at North
Devon District Hospital, UK. Conflicts of interest: none declared.
Lucy Miller BM MRCP FRCA is a Consultant in Anaesthesia and Pain
Management at North Devon District Hospital, UK. Conflicts of
interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Please cite this article in press as: Thomson L, et al., Opioids in the management of persistent non-cancer pain, Anaesthesia and intensive care
medicine (2016), Descargado de ClinicalKey.es desde PONTIFICIA UNIVERSIDAD JAVERIANA octubre 12, 2016.
http://dx.doi.org/10.1016/j.mpaic.2016.08.008
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados.
Learning objectives
After reading this article, you should:
C
C
appreciate the role of opioids in the treatment of PNCP
be aware of the adverse effects associated with the long-term
use of opioids
C be able to outline best practice when initiating opioids in the
management of PNCP
C be able to list commonly used modified release opioids and the
morphine equivalent doses
system. Despite this increase, PNCP associated disability remains
high. European studies have shown that 30e40% of patients
who were prescribed opioids reported inadequate pain relief and
were dissatisfied with their long-term outcome.2 Furthermore,
there has been a vast increase in the number of reported cases of
opioid misuse, adverse effects, mortality and dependency.
The use of opioids in the treatment of acute pain, cancer and
end-of-life care is widely acknowledged and clinicians are mostly
comfortable about prescribing in these settings. The focus of
treatment for PNCP is different as it is aimed at improving
physical and mental well-being in combination with the judi-
cious use of appropriate medication. The evidence for the use of
opioids in PNCP remains undetermined and in light of their
knowledge of potential adverse effects, clinicians commonly
express apprehension about initiation and maintenance of
opiates.
Evidence for the efficacy of the use of opioids in PNCP
Meta-analysis of several randomized control trials (RCTs), last-
ing on average 12 weeks, concluded that opioid therapy provided
short- to medium-term pain relief for a number of chronic pain
conditions, when compared to placebo.3 In 2010, a Cochrane
Review also found clinically significant pain relief with opioid
therapy, and that strong opioids can result in an even greater
level of relief.4 However, a high drop-out rate was observed
across the RCTs as it was noted that many patients discontinued
their use of opioids due to adverse effects, insufficient pain relief
and diminished analgesia despite dose escalation. It was further
demonstrated that opioids are not superior to NSAID, tricyclic or
anticonvulsant drugs in decreasing pain or disability.
There are limitations with this RCT data which should be
interpreted with caution. The selected patient cohort often
experienced discrete pain and may not represent the complexity
of persistent pain patients that are seen in practice. Due to the
high drop-out rates, many RCTs adopt a ‘last-observation-car-
ried-forward’ methodology and, as such, patients who withdraw
are presumed to maintain pain relief and are recorded positively.
A recent meta-analysis of RCTs concluded that most opioid trials
do not extend beyond 6 weeks. There were no studies lasting
longer than 1 year that evaluated the effects of pain on function
or quality of life when comparing long-term opioid therapy for
chronic pain versus non-opioid therapies.5 As a result, data
assessing the long-term effects have been generated from open-
label extensions, population and case studies. One such popu-
lation study indicated that long-term opioid users report more
1 Ó 2016 Elsevier Ltd. All rights reserved.
 PAIN

severe pain with poorer quality of life and function.6 Convincing regardless of pain intensity. For those who fail to respond to first-
evidence, therefore, remains insufficient to determine the effec- line treatments, a trial of opioids can be considered to determine
tiveness of long-term opioid use in providing sustained pain relief effectiveness. There is no supporting evidence that one opioid is
and improved function for PNCP. more effective or is associated with fewer adverse affects.
Morphine should be initiated in oral form. Rapid release prepa-
Guidelines for the use opioids in PNCP rations, such as fentanyl (transmucosal or sublingual adminis-
tration) are inappropriate for the management of persistent non-
The British Pain Society recently launched the web-based
cancer pain, and injectable opioids should not be used.
resource Opioids Aware, which is developed by UK healthcare
Typically, a short course (1e2 weeks) of immediate release oral
professionals and is hosted by the Royal College of Anaesthetists.7
morphine tablets or liquid within a specific dose regime, e.g.
It provides resources to guide clinicians in safe and effective
morphine 5e10 mg, can be commenced. If reduction in pain is not
prescribing of opioids. It acknowledges that PNCP is a complex
achieved following a single dose of immediate relief morphine 20
condition that is influenced by many physical and psychosocial
mg, opioids are unlikely to be beneficial in the long-term. For
factors (see Table 1). Patients are at risk of being exposed to
patients experiencing PNCP at night, modified release opioids at
adverse effects of opioids when they are prescribed over pro-
regular intervals may be more appropriate. Opioid rotation or
longed periods. Therefore, it advocates an initial comprehensive
switching may be considered when adequate analgesia is achieved
assessment of the patient to determine specific prescribing needs.
but with intolerable side effects. If pain relief is not achieved during
The WHO pain ladder (1986) was developed for the treatment
the opioid trial, then the medication should be tapered and stopped.
of cancer-related pain and is a step-wise approach relating to
Prior to commencing opioids, assessable outcomes, which
pain intensity. It is not applicable to PNCP due to the persistence
include functional goals, need to be pre-determined and agreed
of ongoing pain and different goal directives. The role of medi-
upon by the patient and prescriber. A reduction in pain by at least
cation in PNCP is less certain than in other types of pain and may
30% should be demonstrated to support long-term prescribing. It
be less effective in practice. Therefore, opioids should be used in
is important to discuss potential adverse effects, as 80% of pa-
combination with other non-pharmacological treatments to
tients taking opioids will experience at least one such effect.
support improved physical, psychological and social functioning.
When a regimen is stable and the patient reports a substantial
Opioids should not be used as first-line therapy when alter-
relief of symptoms, opioid treatment should be reviewed at least
native non-opioid and evidence-based options are available,
six-monthly, and at this time the dose should be tapered to allow
evaluation of continued efficacy. There is no evidence for effi-
cacy of high-dose opioids in long-term pain. Furthermore, the
Approximate dose equivalent analgesic potencies of
risk of harm increases substantially beyond doses equivalent to
opioid preparations for oral and transdermal
oral morphine 120 mg/day.
administration
Oral opioid preparations Equivalent dose to 10 mg
Adverse effects of long-term opioid use
oral morphine
Opioid use is associated with a 50e80% incidence of short- and
Codeine phosphate 100 mg long-term adverse effects.8 These range from dry mouth, pruri-
Dihydrocodeine 100 mg tus, constipation, nausea, drowsiness, weight gain, sleep distur-
Hydromorphone 1.3 mg bance, sexual dysfunction and hyperalgesia, to tolerance,
Morphine 10 mg addiction, withdrawal, hypothalamic-pituitary axis and immu-
Oxycodone 5 mg nological suppression (with buprenorphine as an exception for
Tapentadol 25 mg the latter side effect).
Tramadol 67 mg Nausea, vomiting (prevalence 20%) and sedation (prevalence
29%) are often experienced upon initiation of an opioid treat-
Transdermal opioid preparations Equivalent oral morphine
ment regime, or during dose increases, but generally do not
(microgram/hr) (mg/day)
persist as tolerance develops.7 In comparison, constipation and
Buprenorphine 5 12
urticaria persist. The use of anti-emetics (during the initial
Buprenorphine 10 24
phase), laxatives, patient education and careful titration are
Buprenorphine 20 48
important in order to improve compliance.
Buprenorphine 35 84
Respiratory depression can occur when initial opioid doses
Buprenorphine 52 126
are too high, or are titrated too quickly, or are prescribed in
Buprenorphine 70 168
combination with medication of a similar side-effect profile. Pa-
Fentanyl 12 45
tients with pre-existing sleep apnoea, underlying pulmonary
Fentanyl 25 90
conditions, hepatic and renal impairment may experience
Fentanyl 50 180
increased susceptibility. Careful initiation and titration is
Fentanyl 75 270
imperative in this patient group.
Fentanyl 100 360

(From the Royal College of Anaesthetists Website, with kind permission) Endocrine dysfunction
Opioids inhibit gonadotropin-releasing hormone and corticotro-
Table 1
phin releasing hormones from the hypothalamus resulting in

ANAESTHESIA AND INTENSIVE CARE MEDICINE --:- 2 Ó 2016 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Thomson L, et al., Opioids in the management of persistent non-cancer pain, Anaesthesia and intensive care
medicine (2016), Descargado de ClinicalKey.es desde PONTIFICIA UNIVERSIDAD JAVERIANA octubre 12, 2016.
http://dx.doi.org/10.1016/j.mpaic.2016.08.008
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados.
 PAIN
reduced circulating levels of cortisol, testosterone and oestrogen.
Adrenal insufficiency and hypogonadism as a result of long-term
opioid therapy are seen more commonly in men (75%) compared
to women (21%).9 The risk of developing sex hormone de-
ficiencies is greatest above 100 mg/day morphine equivalent,
and symptoms include reduced libido, erectile dysfunction, fa-
tigue, depression, testicular atrophy, amenorrhoea and infertility.
Lower levels of testosterone also lead to a reduction in bone
mineral density and increased risk of fracture.
Hyperalgesia, tolerance and withdrawal
Prolonged exposure to opioids can lead to nociceptive sensiti-
zation which results in increased levels of pain, known as opioid
induced hyperalgesia (OIH). The reported pain is often different
in site, nature and character to the patient’s pre-existing pain and
is often less well-defined. The mechanism is still unclear and its
prevalence in clinical practice remains relatively unknown;
however, the risk increases significantly above 120 mg morphine
equivalent per day. The optimal treatment is a slow reduction in
opioid doses or changing to an alternative preparation in an
attempt to re-sensitize.
Pharmacological tolerance is likely to develop over time, with
opioid receptors requiring increased doses to initiate the same
analgesic response. Higher doses may overcome tolerance;
however, this may put the patient at an increased risk of adverse
effects including OIH. Opioid withdrawal results from abrupt
cessation of treatment and may lead to symptoms such as
sweating, agitation and abdominal cramps. This is particularly
common with the use of Tramadol and is even demonstrated
after shorter duration use.
Dependence and addiction
Studies suggest 8e12% of long-term prescribed opioid users
meet the criteria for a current or past opioid use disorder. The
associated symptoms vary considerably and range from difficulty
in reducing opioid doses, due to withdrawal side effects, to
complex presentations involving difficult behaviours and psy-
chosocial implications. The former is often described as depen-
dence and the latter as addiction. The heterogeneity of
presentations by patients can lead to difficulties in accessing
appropriate services to support opioid reduction.
Long-term epidemiological data suggest that patients with co-
morbid mental health diagnoses or a history of addiction are
more likely to receive opioids for pain. These are often prescribed
in higher doses, multiple opioid preparations and in addition to
other psychoactive drugs (e.g. benzodiazepines).8
Safety and legislation
Morphine is one of the most frequently reported drugs implicated
in serious medication errors. Data on drug poisoning and misuse-
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Please cite this article in press as: Thomson L, et al., Opioids in the management of persistent non-cancer pain, Anaesthesia and intensive care
medicine (2016), Descargado de ClinicalKey.es desde PONTIFICIA UNIVERSIDAD JAVERIANA octubre 12, 2016.
http://dx.doi.org/10.1016/j.mpaic.2016.08.008
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2016. Elsevier Inc. Todos los derechos reservados.
related deaths show an overall increase in deaths in association
with opioid therapy.10 This risk of accidental and intentional
overdose increases with higher doses of opioid. Recently, over-
dose of controlled drugs has accounted for 69.5% of reported
serious harm (death and severe harm) incidents.
Although opiate use does not specifically preclude patients
form driving, it remains illegal to drive in England and Wales
when taking any prescription medicines that are known to impair
a patient’s ability to drive. Assessment of safe driving ability at
present remains with the patient. Morphine and methadone have
specified limits (morphine 80 mg/l); however, prescribers should
be aware of equi-potent doses of other opioids. Cautionary
advice related to driving safety should be clear and should be
documented, particularly at initiation and at times of dose
adjustment. A
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3 Ó 2016 Elsevier Ltd. All rights reserved.