MANAGEMENT OF MIXED PAIN

Gita Pramadewi Fitriani, S.Ked

I1A004017
Department of Internal Medicine, Ulin General Hospital,
Banjarmasin, Kalimantan Selatan, Indonesia

Abstract

From several studies, mixed affects 16% to 37% patients. Mixed pain is defined
as pain with mixed underlying pathophysiology that consist of nociceptive and
neuropathic pain that has its own portion when pain occurs. Nociceptive pain is
pain resulting from pain receptors. While neuropathic pain is a result of injury to
or disease in the nervous system, either in the central or peripheral nervous
system. No pain receptors exist in this type; therefore, the pain is caused by nerve
dysfunction sending signals. Mixed is a challenge for any practitioner to treat that
it may cause patients still feeling the pain after taken drug’s prescriptions.
Therefore, its important to understand the main pathophysiology and most
suitable drugs that should be prescribed by doctor. This article would reviewed
about about management of mixed pain based on underlying pathophysiology.

Keywords: mixed pain, nociceptive pain, neuropathic pain

Introduction

Although pain of mixed pathophysiology is a poorly recognized entity,

this condition affects many patien from several studies indicate that the

prevalence of pain of mixed pathophysiology among patients with ranges from

16% to 37%. In a prospective, multicenter epidemiologic survey of nearly 8000

patients with chronic low back pain, 30% nociceptive pain component, 37% had a

neuropathic pain component, and 28% had a combination of pain components.1 A

prospective study of 129 patients with advanced solid cancers presenting to a

palliative medicine can suggesting that the chronic pain in this patient group had a

1
mixed nociceptive and neuropathic pathophophysiology. Of the remaining

patients, 52% had somatic nociceptive pain, 22% had visceral pain, and 10% had

neuropathic pain. While in the questionnaire phase of the study that included 586

patients with chronic nonheadache pain, specialists determined that 69% of

patients had nociceptive pain, 15% had neuropathic pain, and 17% had

pathophysiology.2 A survey of 228 opioid-treated patients with diverse types of

chronic noncancer pain determined that 37 pain of mixed etiology.1

Definition

The International Association for the Study of Pain defines pain as an

unpleasant sensory and emotional experience associated with actual or potential

tissue damage, or described in terms of such damage.3 While mixed is defined as

pain with mixed underlying pathophysiology that consist of nociceptive and

neuropathic pain that has its own portion when pain occurs.1

Nociceptive pain is pain resulting from pain receptors. When a pain

receptor is stimulated, such as being burned or cut, the pain receptors send signals

to the brain so the body can take action, either by removing you from danger or

receiving medical aid. Somatic and visceral pain respond to heat and cold as well

as vibrations, stretching and chemical interactions. Somatic pain is referred to as

musculoskeletal pain. It is found in tissue such as skin and muscles as well as in

joints, bones and ligaments. Somatic pain is often characterized as a sharp pain

localized in a specific area of injury. Swelling, cramping and bleeding may exist

with somatic pain. This classification of pain responds to a variety of medications,

including opioids and nonsteroidal anti-inflammatory drugs. Visceral pain is

anther type of nociceptive pain located within the main body cavity due to injury

or illness to an internal organ. The three main centers for visceral pain are the

thorax, abdomen and pelvis. The pain receptors in the visceral cavities respond to

stretching, swelling and oxygen deprivation. Opioids are the most effective pain

medication for this classification of pain, which feels like a deep ache with

cramping. Visceral pain may radiate to other locations in the back and chest.4

Non-nociceptive pain stems from a problem in the central or peripheral

nervous system. No pain receptors exist in these two systems; therefore, the pain

is caused by nerve dysfunction sending signals.4 This may called neuropathic

pain. Neuropathic pain is a result of injury to or disease in the nervous system.

Diabetic peripheral neuropathy is a painful complication of diabetes that results in

nerve pain. Postherpetic neuralgia (PHN) is a recurring or persistent pain after

shingles infection. Trigeminal neuralgia involves nerve pain of the face.

Compression neuropathies cause significant nerve pain due to nerve compression.

Amputation can leave phantom limb pain, which is neuropathic pain. Multiple

sclerosis attacks cause widespread nerve pain based on where the disease attacks

the brain. Drugs, such as those used in chemotherapy, can cause nerve pain.

Complex regional pain syndrome is a neurological condition that causes

significant nerve pain.5

Neuropathic pain may be caused by lesions of nociceptive sprouts within

the degenerated disc (local neuropathic), mechanical compression of the nerve

root (mechanical neuropathic root pain), or by action of inflammatory mediators

(inflammatory neuropathic root pain) originating from the degenerative disc even

without any mechanical compression. Since different pain-generating mechanisms

possibly underlie sciatic pain, the term mixed pain syndrome was established.6

In some conditions the pain appears to be caused by a complex mixture of

nociceptive and neuropathic factors. An initial nervous system dysfunction or

injury may trigger the neural release of inflammatory mediators and subsequent

neurogenic inflammation. For example, migraine headaches probably represent a

mixture of neuropathic and nociceptive pain. Myofascial pain is probably

secondary to nociceptive input from the muscles, but the abnormal muscle activity

may be the result of neuropathic conditions.7

Pathophysiology

The pathophysiology of acute or chronic pain is typically categorized as

nociceptive or neuropathic pain from the activation of pain-sensing neurons (eg,

nociceptors) by noxious mechanical, chemical, or therm described as throbbing,

constant, aching, cramping, and/or sharp, depending on the cause of pain.

Common sources of nociceptive pain include bone fractures, arthritis, and pain

following surgical proced nociceptive pain, neuropathic pain constitutes pain that

is initiated or caused by disease or dysfunction Neuropathic pain may be

described as shooting, burning, sharp, numb, and/or a deep, dull, bonelike

neuralgia, trigeminal neuralgia, and radiculopathy are examples of neuropathic

pain. Although usually not formally recognized as a distinct class of pain, pain
consisting of both nociceptive a quite common among patients with a variety of

chronic pain conditions.1,8

Chronic pain presents several management challenges due to its complex

pathophysiology. This complete differentiating between chronic nociceptive pain

and chronic neuropathic pain, as well as from alteration and description of chronic

pain over time.1,9 Pain that is initially nociceptive can transition to neuropath or a

deep cut may cause nerve damage that persists long after the wound itself has

healed, leading to similarly, pain that is initially neuropathic may transition to

acquire a nociceptive component. For exam postherpetic neuralgia may move

differently during daily activities due to neuropathic pain.1,10

 Figure 1. Nociception transmission pathway (top) and nociceptors causing
hyper algesia bottom.11,12

Many patients suffer from chronic pain with a mixed pathophysiology that

comprises both nociceptive an components. Common examples of chronic pain

with a mixed pathophysiology include low back musculoskeletal pain, and

complex regional pain syndrome.1,2,8,9,10,13,14 Chronic low back pain represents a

pathophysiology: the back itself may hurt due to activation of nociceptors

innervating ligaments, small joint (nociceptive pain), while mechanical

compression of spinal nerves may cause radiculopathy in which bu (neuropathic

pain).1,2 Chronic pain associated with cancer is another classic example of chronic

pai pathophysiology.1,14 A growing tumor may activate nociceptive receptors

through tissue damage or the substances while also causing neuropathic pain

through tumor infiltration and compression.14 Result in pain of mixed

pathophysiology include spondylosis, spondylolisthesis, spondylitis, osteoporosis

bone fracture.1

Clinical assessment

The goal of the initial assessment of pain is to characterize the

pathophysiology of the pain and to determine the intensity of the pain and its

impact on the patient’s ability to function. Factors that may influence analgesic

response and result in persistent pain include changing nociception due to disease

progression, intractable side effects, tolerance, neuropathic pain, and opioid

metabolites. The following are essential to the initial assessment: 1) Detailed

history; 2) Physical examination; 3) Psychosocial assessment;[8] and 4)

Diagnostic evaluation.3

The mainstay of pain assessment is the patient self-report; however, family

caregivers are often used as proxies for patient reports, especially in situations in

which communication barriers exist, such as cognitive impairment or language

difficulties. Family members who act as proxies typically, as a group, report

higher levels of pain than patient self-reports, but there is individual variation. To

enhance pain management across all settings, clinicians should teach families to

use pain assessment tools in their homes. The clinician should help the patient to

describe: 1) Pain characteristics; 2) Location; 3) Changes in Pattern; 4) Intensity

or severity; 5) Aggravating and relieving factors; 6) Cognitive response to pain;

and 7) Cognitive impairment.3

 Figure 2. Arthritis is one of possible causes of pain. Any pain locating to
these site should be considered as arthritis.15

A thorough physical examination is required to determine the

pathophysiology of pain. Specific features of the neurologic examination such as

altered sensation (hypoesthesia, hyperesthesia, hyperpathia, allodynia) in a painful

area are suggestive of neuropathic pain. Physical findings of tumor growth and

metastasis are also important to identify.3

Pharmacologic management

Basic principles

The World Health Organization (WHO) has described a three-step

analgesic ladder as a framework for pain management. It involves a stepped

approach based on the severity of the pain. If the pain is mild, one may begin by
prescribing a Step 1 analgesic such as acetaminophen or a nonsteroidal anti-

inflammatory drug (NSAID). Potential adverse effects should be noted,

particularly the renal and gastrointestinal adverse effects of the NSAIDs. If pain

persists or worsens despite appropriate dose increases, a change to a Step 2 or

Step 3 analgesic is indicated.3

Figure 3. NSAIDs are the cornerstone of analgesia, providing relief from

everyday pains such as headache, toothache, muscular aches, mild joint pain
and period pain.16

Most patients with cancer pain will require a Step 2 or Step 3 analgesic.

Step 1 can be skipped in those patients presenting at the onset with moderate-to-

severe pain in favor of Step 2 or Step 3. At each step, an adjuvant drug or

modality such as radiation therapy may be considered in selected patients. WHO

recommendations are based on worldwide availability of drugs and not strictly on

pharmacology. Analgesics should be given “by mouth, by the clock, by the ladder,

and for the individual.” This requires regular scheduling of the analgesic, not just

as needed. In addition, rescue-doses for breakthrough pain need to be added. The

oral route is preferred as long as a patient is able to swallow. Each analgesic

regimen should be adjusted for each patient’s individual circumstances and

physical condition.3

Step 1: Acetaminophen and nonsteroidal anti-inflammatory drugs

NSAIDs are effective for relief of mild pain and may have an opioid dose–

sparing effect that helps reduce side effects when given with opioids for

moderate-to-severe pain. Acetaminophen is included with aspirin and other

NSAIDs because it has similar analgesic potency, though it lacks peripheral anti-

inflammatory activity. Side effects can occur at any time, and patients who take

acetaminophen or NSAIDs, especially elderly patients, should be followed

carefully. There is growing debate about whether NSAIDs are useful and have

significant opioid-sparing effects. One meta-analysis suggests that the usefulness

of NSAIDs is limited and that they do not significantly spare opioid doses.

Another study suggests that NSAIDs are useful and reduce the need for opioid

dose increases; however, only patients with pain progression after 1 week of

opioid stabilization were selected for the study.3

 Figure 4. HCT-3012-COX-inhibiting nitric oxide-donator (CINOD) for
relief of pain and inflammation. HCT 3012 is indicated for the treatment of
acute and chronic nociceptive pain, such as post-operative and arthritic
pain.17

The coxibs are a subclass of NSAIDs designed to selectively inhibit

cyclooxygenase-2 (COX-2). Development of these drugs was based on the

hypothesis that COX-2 was the source of prostaglandins E2 and I2, which mediate

inflammation, and COX-1 was the source of the same prostaglandins in gastric

epithelium, with the potential advantage over traditional NSAIDs of less

gastrointestinal ulceration and bleeding and the absence of platelet inhibition.

Direct comparisons between COX-2 inhibitors are few. A systematic meta-

analysis of COX-2 inhibitors compared with traditional. NSAIDs or different

COX-2 inhibitors for postoperative pain suggests that rofecoxib, 50 mg, and

parecoxib, 40 mg, are equipotent to traditional NSAIDs for postoperative pain

after minor and major surgical procedures and have a longer duration of action

after dental surgery. Rofecoxib was found to provide superior analgesic effect

compared with celecoxib, 200 mg. There were insufficient data to comment on

toxicity.3

Step 2 and 3: Opioid drugs – partial and/or full morphine-like agonist

Opioids, the major class of analgesics used in management of moderate-

to-severe pain, are effective, are easily titrated, and have a favorable benefit- to-

risk ratio. Opioids are classified as full morphine-like agonists, partial agonists, or

mixed agonist-antagonists, depending on the specific receptors to which they bind

and their activity at these receptors. The benefits of using opioids and the risks

associated with their use vary among individuals.The predictable consequences of

long-term opioid administration—tolerance and physical dependence—are often

confused with psychological dependence (addiction) that manifests as drug abuse.

This misunderstanding can lead to ineffective prescribing, administering, or

dispensing of opioids for cancer pain. The result is undertreatment of pain.3

Most patients with cancer pain require fixed-schedule dosing to manage

the constant pain and prevent the pain from worsening. An Italian study of

patients whose baseline pain was well controlled on morphine when admitted to a

palliative care unit found that most episodes of breakthrough pain were rapidly

controlled with IV morphine equivalent to 20% of the calculated equianalgesic

total daily dose. Adverse effects were uncommon. An as-needed rescue dose

(breakthrough dose) should be combined with the regular fixed-schedule opioid to

control the episodic exacerbation of pain, often referred to as breakthrough pain.

When this pain is elicited by an action such as weight-bearing, breathing, or

defecation, it is termed incident pain.3

Rescue or breakthrough doses can be given hourly or more frequently as

needed, depending on route of administration, pharmacokinetic properties of the

drug, and presence or absence of side effects. The breakthrough dose is generally

calculated to be 10% to 20% of the total dose of the fixed schedule. Adherence

rates are improved when patients are prescribed around-the-clock opioids

compared with as-needed prescribing. Preliminary data suggest that the intensity

of incident pain related to bone metastases may be diminished by increasing the

dose of the scheduled opioid above that needed for control of baseline pain, while

maintaining it below that associated with the development of limiting side

effects.3

Adjuvant drugs

Adjuvant drugs are valuable during all phases of pain management to

enhance analgesic efficacy, treat concurrent symptoms, and provide independent

analgesia for specific types of pain. Adverse drug reactions are common,

however, and there are wide interindividual and ethnic differences in drug

metabolism. A survey on symptom severity and management in 593 cancer

patients treated for an average of 51 days reported that during this time,
anticonvulsants were used in 11.8% of patients, antidepressants in 16%,

corticosteroids in 28%, and bisphosphonates in 7.3%. Patients with advanced

cancer on palliative medicine services are reported to receive on average five

medications for symptom relief, and as a result are at high risk of drug

interactions.3

A further note of caution appears in another study that questioned the

concept of opioid-sparing effects of co-analgesics. Nevertheless, adjuvant

analgesics have been extensively studied and reviewed in noncancer settings and

are generally endorsed as an important intervention in the provision of adequate

pain management. Few trials compare adjuvant analgesics in the cancer setting.

Adjuvant medications with possible analgesic activity are antidepressants,

anticonvulsants, local anesthetics, corticosteroids, biphosphonates, baclofen,

calcitonin, clonidine and many others.3

Treatment approach to chronic pain of mixed pathophysiology

Optimal therapeutic management of chronic pain first requires a detailed

pain assessment that involves determining the scope of pain, taking a patient

history, and conducting a physical examination and othe information is then used

to diagnose the pain condition or type, including determining the probable path

identifying the probable pathophysiology of chronic pain may be complicated

when the etiology involves neuropathic components.1,9 The terms used by patients

to describe their pain are subjectively base cannot be confirmed diagnostically.1

Moreover, patients may use the same terms to describe both nocic etiologies.2
 Since it may be difficult to discern whether an individual patient may have

a neuropathic component to t vice versa, it may be prudent to offer therapy that

addresses the mechanisms involved in both pain path effective pain relief.1,18

Moreover, management of pain should endeavor not only to alleviate the ph help

improve physical functioning, reduce psychological distress, and optimize overall

quality of life for comprehensive management of complex chronic pain that

involves targeting different pain mechanisms while minimizing the adverse

effects of medications.1

In accord with a comprehensive approach to pain management, chronic

pain of mixed pathophysiology demamnd pharmacotherapy targeting coexisting

pain mechanisms to alleviate both the nociceptive and neuropathic pain. Opioids

constitute the mainstay of treatment for moderate to severe forms of pain. Most

opioids execute binding to µ-opioid receptors in the brain and spinal cord, thereby

modulating the transmission of nocice opioids have demonstrated efficacy in

clinical trials for the treatment of neuropathic pain, these agents a second-line

treatment due to short- and long-term side effects associated with the relatively

high dosing neuropathic pain by many patients. Instead, pain of neuropathic origin

is often initially treated, primarily before treating other medical conditions,

including some types of anticonvulsants (eg, gabapenti reuptake inhibitors

(SNRIs), and tricyclic antidepressants. Some of these therapies enhance the

inhibitor preventing the reuptake of serotonin and norepinephrine at neural

synapses, thereby inhibiting the tran spinal dorsal horn.1

 A multimodal approach to pain management can help to more fully

alleviate pain by acting through comp to provide additive analgesic effects. A

multimodal approach might entail inhibiting the transmission of higher centers

within the central nervous system, while simultaneously enhancing descending

signals fr that modulate and inhibit synaptic pain transmission at the dorsal horn.

Targeting neurotransmitter posterior horn may not only potentiate the effects of

neurochemicals that inhibit the transmission of nociceptive im opioids, serotonin,

and norepinephrine), it may also dampen the firing of dorsal horn neurons that

becom pain conditions.1,18

Physical and cognitive –behavioral interventions

Patients should be encouraged to remain active and participate in self-care

when possible. Noninvasive physical and psychosocial modalities can be used

concurrently with drugs and other interventions to manage pain during all phases

of treatment. The effectiveness of these modalities depends on the patient’s

participation and communication of which methods best alleviate pain. Minority

patients of various ethnicities have been noted to experience worse control of their

pain, which may result from miscommunication issues within the medical setting.

In a post hoc analysis of a small trial, minority (various ethnicities) (n = 15) and

white (n = 52) cancer patients were randomly assigned either to a 20-minute

individualized education- and-coaching session regarding pain management

(including how to discuss their concerns with their physician) or to usual care.3
 At baseline, minority patients reported significantly more pain than white

patients (6.0 vs. 5.0), whereas at follow-up, disparities had been eliminated in the

intervention group (4.0 vs. 4.3) but remained in the control group (6.4 vs. 4.7).

Physical modalities include therapy using heat, cold, massage-pressure-vibration,

exercise, repositioing, immobilization, and stimulation. While cogitive-behavioral

intervention include relaxation and imagery, hypnosis, cognitive distraction and

reframing, and psychotherapy.3

Conclusion

Pain featuring both nociceptive and neuropathic components may affect up

to one-third of individuals mechanisms underlying pain perception are highly

complex, involving both ascending signals that trans the brain and descending

signals that convey information from higher brain centers to modulate the

transpinal cord. Targeting different aspects of these ascending and descending

pathways with multi overall chronic pain relief than focusing on just one aspect

alone, particularly in chronic pain of mixed pain nociceptive and neuropathic

components contribute to the pain state via different mechanisms.

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