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Journal of Pediatric Hematology/Oncology:
doi: 10.1097/MPH.0b013e31821218a7
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Pathophysiology of Pain in Cancer

von Gunten, Charles F. MD, PhD, Provost

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Institute for Palliative Medicine at San Diego Hospice Third Avenue, San Diego, CA

Reprints: Charles F. von Gunten, MD, PhD, Institute for Palliative Medicine at San Diego Hospice, 4311 Third Avenue, San Diego, California, 92103 USA (e-mail: cvongunten@sdhospice.org).

Received January 12, 2011

Accepted January 24, 2011

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Abstract

Contemporary management of pain is guided by a contemporary understanding of the pathophysiology of pain. Treatment modalities are chosen based on the demonstrated or presumed pathophysiology of cancer pain. When rational oral polypharmacy is used, cancer pain is controlled to the patient's satisfaction 70%-90% of the time.

Cancer frequently causes pain. Although some types of cancer may be untreatable, the associated pain can nearly always be treated to the patient's satisfaction. This requires an understanding of the pathophysiology of pain and the pharmacology of its management. It is the purpose of this paper to review these concepts. This paper may form the basis for cancer pain management programs as part of more comprehensive programs of palliative care (Fig. 1).

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SENSING PAIN

Pain is an adverse sensory experience due to the destruction of normal tissue or described in such terms; “tearing, ripping, like-a-knife are common descriptions”. The human nervous system is designed to sense pain through the nervous system. Nociceptors—specific structures designed to sense pain—are present at the ends of nerves in skin, bones, connective tissues, and organs. The pain stimulus is modulated through several systems of nerves. Pain sensations are sent to the spinal cord through A-δ fibers and C fibers. The A-δ fibers are myelinated and transmit pain signals quickly. The C fibers are unmyelinated and transmit signals more slowly. These 2 different kinds of fibers can be illustrated by remembering the last time you were struck on the leg. There is an initial sense of pain, probably associated with a reflex movement to pull your leg away from the source of injury. Those are the A-δ fibers. Then, a second or two later, a much worse pain seems to be all over the leg and may be associated with a sense of nausea. Those are the C fibers.

A variety of neurotransmitters modulate those pain sensations at the level of the synapses: serotonin, noradrenaline, prostaglandins, substance P, endorphins, and enkephalins are among them. These neurotransmitters are active at the level of the nociceptors and at the level of the spinal cord and the brain.

Some of these neurotransmitters amplify or make the pain stimulus worse. An example is the prostaglandins produced at the sight of an infection or a tumor metastasis. Other neurotransmitters make the pain stimulus less. An example is the opioid-like endorphins. Pharmacologic and nonpharmacologic strategies affect those neurotransmitters. For example, corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with the production of prostaglandins, relieving nociceptive pain. Opioids (such as morphine) act similar to endorphins and enkephalins and relieve pain.

Pain is categorized in 2 broad categories; nociceptive and neuropathic. Pain pathophysiology can usually be inferred from the history, physical findings, and the results of laboratory tests and imaging studies.

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NOCICEPTIVE PAIN

Nociceptive pain is due to stimulation of normal pain receptors (nociceptors) in the peripheral nervous system that are meant to detect tissue damage from mechanical (pressure or stretch), chemical, and thermal stimuli.

Some core characteristics of nociceptive pain include:

Mediation through the direct stimulation of nociceptors (located in skin, muscle, joints, and visceral tissues).

Transmission along neural pathways (afferent system including A-δ and C nerve fibers) through the dorsal horn of the spinal cord and on to ascending neural pathways to the thalamic and other centers in the brain.

Nociceptive pain can be either acute or chronic. Acute pain often follows a readily identifiable event, such as a surgical operation, and resolves within 6 weeks. Chronic pain lasts longer than acute pain. Chronic nociceptive pain comes from continued stimulation of intact nociceptors, such as from a cancer that cannot be removed or has spread.

Nociceptive pain can be further subdivided into somatic and visceral pain based on the location of the nociceptors. Somatic pain is from stimulation of nociceptors in the somatic nervous system of the skin, muscle, bones, and integuments. A patient with somatic nociceptive pain is able to define the precise location of the pain because of the design of the somatic nervous system. The patient often describes that pain as sharp, knife like, aching, or throbbing. Examples include the skin in which an incision has been made, the site of a bone metastasis, or a skin burn from radiation.

Visceral pain is from stimulation of nociceptors on visceral organs such as intestines, spleen, liver, etc. The autonomic nervous system is principally involved in this type of pain. In contrast with somatic pain in the somatic nervous system, visceral pain is associated with the patient reporting that they have trouble describing or localizing the pain. This is because the autonomic nervous system is frequently unmyelinated and highly crosslinked in plexuses. The pain may be described as involving an entire region of the body, such as the entire abdomen. When patients can describe the pain, it may be crampy or gnawing. The pain may be referred; for example, a patient with a liver enlarged by cancer metastases may report that the shoulder hurts.

Local inflammation plays a role in nociceptive pain through several mechanisms: the release of prostaglandins, substance P, serotonin, histamine, acetylcholine, and bradykinin. These chemicals increase the sensitivity of nociceptors by causing influx of calcium ions into the nociceptor. These neurotransmitters also bind to postsynaptic receptors that stimulate an increase in the permeability of sodium and potassium. The result is subthreshold depolarization. This makes the postsynaptic threshold easier to be reached, making it easier to transmit an impulse when neurotransmitter-filled vesicles are released from the presynaptic nerve endings. An additional consequence is the recruitment of nociceptors that were earlier silent in activity. The consequence is that the person feels more pain. Teleologically, the explanation is that the body uses pain as a warning system to protect the area and not subject it to further injury while it tries to heal.

The spinothalamic tract receives input from peripheral nerves and transmits noxious stimuli, nondiscriminative touch, pressure, and temperature. The spinothalamic tract contains second-order neurons, the cell bodies of which are in the contralateral dorsal horn. On entering the dorsal horn, the neurons decussate through the ventral white commissure to the other side of the spinal cord. Thus, they end up ventral to the central spinal canal and hence join the spinothalamic tract.

Spinothalamic tract neurons ascend to the midbrain where they run close to the medial lemniscus and, therefore, are called the spinal lemniscus. Most fibers then continue to the ventral posterior nucleus of the thalamus where they synapse to become third-order neurons, which then ascend to the somatosensory cortex in the postcentral gyrus of the cerebrum. In the cerebral cortex, the body is highly organized in a somatotopical manner.

Unmyelinated C fibers project to the brain stem where they terminate in the reticular formation, especially in the medulla oblongata. The fibers are then known as reticulothalamic fibers as they then continue to the intralaminar nuclei of the thalamus. From here, third-order neurons go to the cerebral cortex, just as with the spinothalamic tract.

The reflexive withdrawal of a limb after acute pain is due to the primary afferent neurons that detected the pain exciting interneurons in the gray matter of the spinal cord. These, in turn, synapse with α motor neurons of the flexor muscles, causing the muscle to contract (flex) and withdraw from the stimulus. If the flexion involves many joints, there is coordination between many spinal segments by “collateralization of primary afferents and interneurons.” There is a crossed extensor reflex that allows flexion of a weight-bearing limb with a balanced extensor reflex of the collateral limb to allow it to take the full body weight momentarily. This is what occurs if you step on a pin: you flex the limb you hurt and extend the other limb to allow it to take your weight.

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NEUROPATHIC PAIN

Neuropathic pain results from pathophysiological changes to the peripheral or central nervous system The changes to the peripheral nervous system may be caused by trauma (such as a surgical operation), distortion (such as the invasion of normal structures by the cancer), cancer treatment (such as chemotherapy or radiation therapy), attempts of the nervous system to respond or regrow after damage, or even unrelieved pain. Central nervous system changes include sensitization (the nervous system feels more pain) and central pain syndromes (the brain, itself, is the source of the pain). In contrast with nociceptive pain, the cause of neuropathic pain may be difficult to identify.

Changes in the peripheral nervous system involve changes in sodium channels that promote ectopic activity. In addition, the excitatory amino acid pathways in the spinal cord are stimulated, chief among these being glutamate. The N-methyl-D-aspartate receptor is stimulated by glutamate and enhances pain transmission. In other words, not all the nerves involved in neuropathic pain are damaged. Rather, the compensatory mechanisms throughout the nervous system lead to abnormal function—feeling more pain than would ordinarily be the case if all of the nerves were responding normally. In other words, the abnormal signaling system has been set up whereby a noxious or non-noxious stimulus generates a larger than expected response. This facilitated sensory state partially explains the neuropathic clinical phenomenon of allodynia.

Core features of neuropathic pain include

* Disordered peripheral or central nerve function.

* Damage to the nerve including compression, transection, infiltration, ischemia, or metabolic injury.

* Descriptions such as burning, tingling, shooting, or electric like.

* Association with allodynia (a nonpainful stimulus like a feather causes pain) and hyperalgesia (an increased response to a noxious stimulus such as a pin prick).

* Association with numbness and sensory changes (the arm feels different where it hurts).

* Pain may exceeds observable injury.

Cancer is associated with a variety of neuropathic pain syndromes:

* Chemotherapy-induced neuropathy (similar to diabetic neuropathy)

* Phantom limb pain (patient feels pain in the limb that has been amputated)

* Postmastectomy pain (burning pain in the scar where there is no evidence of cancer)

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PAIN ASSESSMENT

There are 7 cardinal features of pain assessment:

1. Location: Where does it hurt? Use a body outline chart for precision, which is easy for patients to use. Cancer patients frequently have many pains—elicit a description for each.

2. Quality: What does it feel like? Something like “shooting, burning, pins, and needles” help diagnose a neuropathic component. Words such as, “its hard to describe; it hurts everywhere” suggest more than simple nociceptive somatic pain. Describe each separate pain that the patient is experiencing.

3. Intensity: How bad is it? Use a scoring system. Data are quite clear that, for a given patient, scoring will be quite consistent over time.

(a) Numerical Scale: For example, 0-10 where 10 is the “worst possible pain” (Fig. 2)

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(b) Visual analog scale in which a patient indicates pain with a mark on a 100 mm line (horizontal or vertical) delimited by descriptors (none to worst possible to pain). Pain is reported as the measurement, for example 67 (Fig. 3)

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(c) Word scale: Particularly good for concrete thinkers who cannot describe pain in terms of a number.

(d) Faces scale: Particularly useful for children, the elderly, and those who do not speak your language (Fig. 4).

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4. Temporal pattern; When does it occur (including impact on sleep)? How long does it last?

5. Radiation: Where does the pain go?

6. Exacerbating and relieving factors: What makes it better? What makes it worse? What medications are you taking for the pain (prescription and over-the-counter)? What effect do they have?

7. Meaning: What does the pain mean to you? For many patients with cancer pain, the pain means that the cancer is getting worse, or the person will die soon, or that the person will not be able to work. In other words, pain is not the same as the suffering caused by the pain. Inquire about the emotional, social, and spiritual dimensions (Fig. 5).

Figure 5
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MANAGEMENT OF PAIN

Management of pain should begin once it is identified and characterized. Treatment need not wait until final diagnosis or a comprehensive understanding of its etiology. The traditional teaching that if pain is treated pharmacologically it will mask an accurate diagnosis has been shown to be false. If anything, treatment of pain aids in helping the patient to participate in diagnostic testing.

Pain management varies. For acute pain, the goal is to relieve pain intensity quickly and titrate the medications to the course of the pain, which varies over hours to days. In contrast, for chronic pain, the goal is to prevent the pain rather than wait for the pain to reemerge.

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Consequences of Unmanaged Pain

It was traditionally taught that pain is only a symptom, unimportant except as a guide to diagnosis and treatment. We now know that unmanaged pain has pathophysiological consequences. Chronic pain leads to changes in the nervous system that increases the pain intensity and diminishes the effectiveness in treatment. In other words, some intractable pain syndromes are iatrogenic; a consequence of unmanaged or undermanaged pain. In addition, unrelieved pain can have devastating psychological, practical, and spiritual effects on the individual and family.

Most cancer pain management strategies will require:

* A combination of pharmacologic and nonpharmacologic interventions

* Education of the patient, family, and all caregivers about the plan

* Ongoing assessment of treatment outcomes

Pharmacologic pain management can be thought to comprise 3 components: nonopioid medications, opioid medications, and adjuvant analgesic medications. The nonopioids include NSAIDS, salicylates, and acetaminophen (paracetamol). The adjuvants include medicines that can assist in managing pain but are not primarily analgesics, classes of drugs such as corticosteroids, antidepressants, and antiepileptics.

If pain does not come under control, ask for help. Pain management is improved when using an interdisciplinary team. Such a team may include a nurse, pharmacist, social worker, chaplain, physiotherapist, occupational therapist, child life specialist, and others.

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PRINCIPLES OF PAIN CONTROL AND ANALGESIC THERAPY

There are a number of principles that can be applied in any setting for the management of pain control. First, include pain control as part of the comprehensive evaluation and management of cancer. Assess and manage the physical, psychological (emotional), social (practical), and spiritual dimensions of cancer pain. Manage the pain at the same time as identifying and treating the cause of the pain, when possible. Individualize pain control—no one approach manages all pain. Do not use placebos. Select the simplest approaches. Combine pharmacologic and nonpharmacologic modalities. Obtain the input of consultants when there is uncertainty or if initial attempts are unsuccessful.

The World Health Organization (WHO) has developed a simple, well-tested, 3-step model to help guide the management of cancer pain (Fig. 6).

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* For mild pain (generally 1 to 3 of 10 on a numerical analog scale), start at step 1.

* For moderate pain (generally 4 to 6 of 10), start at step 2.

* For severe pain (7 to 10 of 10), start at step 3.

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Step 1 Analgesics

The nonopioid analgesics that characterize step 1 of the WHO ladder all have a ceiling effect to their analgesia; a maximum dose past which no more analgesia can be expected, but toxicity can be expected.

The nonopioid analgesics (step 1 drugs) act by prostaglandin inhibition. Prostaglandins have an important regulatory role in homeostasis and disease. Since the demonstration that prostaglandin synthase (cyclooxygenase, COX) was inhibited by aspirin (acetylsalicylic acid) in 1971, COX inhibition has been the target for pharmacologic intervention. This understanding of the mechanism of action of aspirin led to the development of the newer NSAIDs.

The noninducible COX-1 isozyme functions to produce prostaglandins involved in homeostasis (gastric cytoprotection, renal function). The inducible COX-2 isozyme in humans opposes and modulates the effects of thromboxane on vascular tone and platelet function in vivo. COX-3 acts centrally as an analgesic-antipyretic, existing solely within the blood-brain barrier. Nonselective NSAIDs, such as ibuprofen and naproxen, inhibit all 3 isoforms. Selective agents (celecoxib) inhibit COX-2 and COX-3. The mechanism by which acetaminophen reduces fever and pain is still a source of debate.

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Analgesics (Step 1 Drugs)

Analgesics include acetaminophen/paracetamol. Acetaminophen is a safe and effective step 1 analgesic. It may also be a useful coanalgesic. Interestingly, its site and mechanism of action are not known, although it is presumed to act centrally. Acetaminophen does not have significant anti-inflammatory effects. Metabolism in the liver creates a reactive metabolite that can cause liver damage if glutathione stores are depleted (severe malnutrition). Chronic doses >4.0 g in 24 hours or acute doses >6.0 g in 24 hours are not recommended. Hepatic disease, heavy alcohol use, and concomitant warfarin usage are relative contraindications.

NSAIDs (including aspirin) are effective step 1 analgesics. They may also be useful coanalgesics. The doses to achieve analgesia may be lower than the doses to be anti-inflammatory. They work, at least in part, by inhibiting COX, the enzyme that converts arachidonic acid to inflammatory prostaglandins.

Prostaglandins affect synaptic transmission in the spinal cord and also synaptic transmission contributing to inflammatory pain in peripheral tissues; therefore, COX inhibitors such as aspirin and NSAIDs may have both peripheral and central nervous system actions relevant to analgesia. NSAIDs decrease pain meditated through stimulus at nociceptors. Moreover, there is a group of nociceptors that are recruited to fire only when exposed to inflammation. This may explain why NSAIDs may be so useful in conjunction with opioids for severe pain.

Side Effects: NSAIDs have a significant incidence of serious and potentially fatal problems. The incidence of death from gastric bleeding after at least 2 months exposure to oral NSAIDs is estimated to be 1 in 1200. The incidence of renal dysfunction is not known. NSAIDs frequently cause fluid retention, and seem to have some cardiovascular side effects—particularly COX 2 inhibitors.

Limiting Side Effects: Patients receiving an NSAID who are at risk of gastrointestinal side effects should be prescribed misoprostol (200 mcg, 2 or 3 times a day) or omeprazole (20 mg once a day).

Some patients are more at risk of serious gastrointestinal side effects from NSAIDs than others. Groups shown to be at high risk are the elderly (>60 y old), smokers, patients with a history of peptic ulcer, taking oral steroids or anticoagulants, and existing renal disease, cardiac failure, or hepatic impairment.

Misoprostol has been proven to reduce the risk of both gastric and duodenal ulcerations developing in patients taking NSAIDs and is superior to both ranitidine and sucralfate. Lower doses of misoprostol (200 mcg, 2 or 3 times a day) significantly reduce the incidence of NSAID-induced damage while having a lower incidence of side effects (compared with 200 mcg, 4 times a day). These drugs should probably not be prescribed for female patients of childbearing age, because of the abortifacient side effects. Another side effect of misoprostol is diarrhea; people who are constipated due to opioids may find this useful.

Omeprazole (20 mg daily) is also effective in reducing the risk of gastric and duodenal erosions. No trials published to date have compared misoprostol with omeprazole for prevention of NSAID-induced gastropathy. However, omeprazole is significantly more effective than misoprostol in treating gastric or duodenal erosions in patients who have developed these and who need to continue NSAIDs. A dose of 20 mg omeprazole daily was as effective as 40 mg daily.

Routes of Administration: Although intravenous (IV) formulations of NSAIDS are also available (ketorolac), they are no more effective nor are they safer than oral NSAIDS. Similarly, there is no difference in effectiveness between Cox-1 and Cox-2 NSAIDs, and it seems that any differences in side effects between the 2 classes are very small and may not be clinically significant. There is little reason to prescribe any Cox-2 agents that remain on the market.

Summary: NSAIDs show a direct dose response relationship in terms of desired effects and both gastrointestinal and renal adverse effects. Limit on the maximum dose is dictated by an increase in side effects. Beyond this level, little extra benefit is achieved for a large increase in the risk of side effects.

There are several chemical classes of NSAIDs. Some patients respond better to one class than to another, and serial “n of 1” trials may be needed to find one that is best for a given patient. Extended-release products are likely to enhance compliance and adherence.

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Step 2 and 3 Analgesics

Steps 2 and 3 of the WHO ladder involve opioids. They can be characterized by their activities at opioid receptors: μ,κ, and δ. These μ, κ, and δ receptors are found both peripherally and centrally. Opioids may act as full agonist, partial agonist (buprenorphine), or mixed agonist-antagonist (butorphanol, nalbuphine, or dezocine) drugs. They affect intracellular levels of potassium and calcium, modifying a nerve's threshold for firing and its propensity to release neurotransmitters, thereby inhibiting the transmission and perception of nociceptive input.

Most opioids useful for cancer pain management are full agonists. These may be further divided into short acting and long acting, based on their time-action properties. Morphine is short acting and requires frequent doses to maintain analgesia. Extended-release oral (morphine, oxycodone, oxymorphone) and transdermal (fentanyl) formulations and oral opioids with long half-lives (methadone, levorphanol) are preferred for the management of persistent pain.

Opioids are first-line therapy for moderate-to-severe pain in nociceptive, neuropathic, and mixed pain syndromes. For severe neuropathic pain, opioids alone are often insufficient and must be combined with adjuvant analgesics. In fact, an important clinical clue that there may be a neuropathic component to a pain syndrome is when high-dose opioids are unsuccessful in controlling pain.

For the management of common moderate-to-severe pain in opioid-naïve patients who can use oral medications, the usual opioids selected include codeine, hydrocodone, and oxycodone, which in this setting, are in combination products with acetaminophen, aspirin, or ibuprofen. These exhibit a ceiling effect with increasing dose, but most patients experience satisfactory analgesia before this treatment-limiting toxicity occurs.

Codeine is a commonly used μ agonist, but it is usually a poor choice as an analgesic. Codeine seems to produce more constipation and nausea at equianalgesic doses than other pure μ agonists. Furthermore, codeine is the only opioid that is a prodrug (it must be metabolized after ingestion or injection to become active). Some people have an insufficient amount of the hepatic enzyme necessary to metabolize codeine to its active form. Combination products containing oxycodone or hydrocodone do not have the limitations of those that contain codeine.

Step 3 pure opioids do not have a dose limitation, and in fact they have no theoretical ceiling for efficacy or end-organ toxicity. They can be titrated to pain relief limited only by adverse effects; there is no ceiling or highest dose. These include morphine, hydromorphone, oxymorphone, methadone, levorphanol, and fentanyl.

Meperidine (Demerol, others) is metabolized to a neurotoxic metabolite (normeperidine), which has a far longer half-life and can accumulate rapidly, especially in the elderly and those with renal insufficiency. Meperidine has been removed from the formularies of many hospitals because safer alternatives exist.

Propoxyphene is also metabolized to a potentially neurotoxic agent (norpropoxyphene), although to a lesser extent than meperidine. This potential for tremulousness and seizures, and also cardiotoxicity with overdose, increases the risk of this agent. The US Food and Drug Administration recently banned the use of this drug.

Tramadol and tapentadol are special case drugs. Although the exact mechanism of pain relief is unknown, these drugs exhibit weak μ-opioid agonism and inhibitory effects on norepinephrine and serotonin reuptake. The nonopioid effects may mediate its efficacy for neuropathic pain. For moderate pain, concomitant tramadol use may result in analgesia with less opioid side effects, such as constipation. At the recommended doses for analgesia, tramadol is equivalent to 300 mg acetaminophen or 30 mg codeine. Doses of tramadol greater than 400 mg/d are associated with an increased risk of seizures.

Opioids can be administered by a wide variety of routes (each of which has various benefits and risks): oral, sublingual, transmucosal, rectal, transdermal, subcutaneous (SC), intramuscular (IM), IV, epidural, and intrathecal.

Oral administration of opioids is easily absorbed in the gastrointestinal (GI) tract, and they are subjected to first-pass metabolism in the liver. As such, larger doses are required compared with parenteral routes. Most immediate-release oral opioids require 20 to 40 minutes for onset of action, with peak analgesia reaching within 45 to 60 minutes. Rectal administration avoids first -pass metabolism.

IM administration is not generally recommended due to its multiple disadvantages: painful administration, unpredictable absorption, potential for tissue fibrosis and abscesses, and rapid declines in analgesic effect. SC administration provides similar pharmacokinetics with greater patient comfort. The SC route should replace the IM route for opioids.

IV administration is indicated for postoperative pain relief or other circumstances when GI absorption is restricted, patients cannot swallow, or rapid (or closely tailored) effects are desirable. IV administration yields peak analgesia in a range of almost immediately to as long as 20 minutes, depending on the characteristics of the specific drug. Patient-controlled analgesia is one of the most effective means of providing parenteral analgesia.

Neuraxial administration intrathecally or epidurally is reserved for a small subset of patients.

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OPIOID PHARMACOKINETICS

Safe and effective dosing of opioids for cancer pain control is guided by straightforward principles of pharmacokinetics; most of the common drugs follow first-order kinetics. They reach their peak plasma concentration (Cmax) approximately 60 to 90 minutes after oral (including enteral feeding tube) or rectal administration, 30 minutes after SC or IM injection, and 6 minutes after IV injection. Peak plasma concentration correlates with peak pain relief.

The analgesic effect associated with each opioid has a half-life (t

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) that depends both on the rate of liver metabolism and its rate of renal clearance. With 1 exception (methadone, which has a t

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of 15 to 40 h), opioids and their metabolites have effective t

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of approximately 3 to 4 hours, assuming normal renal clearance.

For a patient with chronic cancer pain, prescribe a dose of a pure agonist medication every half-life. Steady-state of blood levels are achieved after 5 half-lives. In other words, for most of the common pure agonist opioids, steady-state of blood levels are achieved after 24 hours.

A rescue dose, generally 10% of the 24-hour dose, can be given every Cmax if pain is incompletely controlled.

If pain remains uncontrolled after 24 hours, increase the routine dose by 25% to 50% for mild-to-moderate pain, by 50% to 100% for severe-to-uncontrolled pain, or by an amount at least equal to the total dose of rescue medication used during the previous 24 hours.

If you have waited 24 hours for the medication to reach a steady state, do not wait any longer. Delays only prolong the patient's pain unnecessarily.

If pain is severe and uncontrolled after 1 or 2 doses (crescendo pain), increase the dose more quickly. Observe the patient closely until the pain is better controlled.

There are many advantages of oral sustained-release formulations of commonly used opioids, which release in a controlled manner over 12 to 24 hours. These require less frequent dosing, which improves patient adherence. The controlled-release formulation requires that the pills not be crushed or chewed; they must be ingested as a whole. Other formulations include extended-release capsules containing time-release granules that can be swallowed whole or the granules can be mixed with fluid and flushed down a feeding or other tube into the upper GI tract.

The extended-release opioids are much more expensive than the immediate-release formulations. In countries with low or moderate resources, adequate pain relief can be obtained with dosing of immediate release, inexpensive drugs such as morphine every 4 hours.

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ADVERSE EFFECTS OF OPIOIDS

Opioids have common and uncommon adverse effects. If unmanaged, they may be a reason for nonadherence or decreased quality of life.

Constipation is the most common side effect of opioids during chronic use. It is primarily the result of opioid effects on myenteric plexus of gut that, in turn, reduce gut motor activity and increase stool transit time. The colon has more time to desiccate its contents, leaving large hard stools that are difficult to pass.

Patients often do not develop pharmacologic tolerance to constipation. Consequently, a bowel regimen should be prescribed with chronic opioid dosing for cancer pain. Dietary interventions alone (increased fluid and fiber) are insufficient. Bulk-forming agents (psyllium) require substantial fluid intake and are not recommended for those with advanced disease and poor mobility.

Peristaltic stimulants (senna, bisacodyl) are routinely recommended, unless use of these agents is contraindicated. Osmotic agents, such as lactulose, are also effective. Stool softeners (docusate sodium) are ineffective by themselves. Methylnaltrexone, a peripheral opioid antagonist, is effective for patients with constipation that persists despite standard laxatives.

Nausea and vomiting is a problem for a substantial minority of patients at the start of opioid therapy. Some patients, however, report persistent nausea during chronic therapy. Young women seem to be most at risk. Nausea usually resolves in 5 to 7 days. An antidopaminergic antiemetic such as prochlorperazine should be prescribed before the first dose of opioid, and routinely for 5 to 7 days in those most disposed to the adverse effect—young women.

Urticaria and pruritus are the result of nonspecific mast cell degranulation by the opioid and subsequent histamine release. Usually, the rash and pruritus can be managed by routine administration of long-acting, nonsedating antihistamines [fexofenadine (60 mg peroral twice a day), diphenhydramine, loratadine, or doxepin (10 to 30 mg peroral every night)], and the opioid may be continued. These do not reflect an antibody-mediated allergic response.

When started, the opioids cause sedation. For most patients, pharmacologic tolerance develops over several days; it does not limit long-term treatment and patients can be reassured that they will not always be sleepy. Patients who have experienced sleep deprivation from uncontrolled pain will experience a period of exhaustion; this is not opioid-induced sedation. If a patient is asleep, but awakes to voice or light touch, the patient is not oversedated from opioids. If undesired sedation persists, a different opioid or an alternate route of administration may provide relief. In addition, consider the use of a psychostimulant (methylphenidate, 5 mg every morning and every noon and titrate), particularly if the opioid is providing effective analgesia. Pain is a potent stimulus of alertness. Once pain is managed, the patient's “natural” level of sedation may become apparent due to advanced cancer.

Respiratory depression is an uncommon adverse effect of opioids for cancer pain control when dosed according to standard guidelines. Many physicians have an exaggerated view of the risk of respiratory depression when using opioids to relieve pain. Pain is a potent stimulus to breathe, and pharmacologic tolerance to respiratory depression develops quickly. Opioid effects of someone in pain are quite different compared with those experienced by a patient who is not in pain and who receives similar doses. As doses increase, respiratory depression does not occur suddenly in the absence of overdose. Somnolence always precedes respiratory depression. Adequate ongoing assessment and appropriate titration of opioids based on pharmacologic principles will prevent misadventures.

Patient-controlled analgesia with an appropriate dosing interval (6 to 15 min if IV, 20 to 30 min if SC) can be used safely, because the patient who takes too many extra doses of opioid will fall asleep and stop pushing the button before respiratory depression occurs.

If respirations do become compromised (<6/min), naloxone may become necessary, if it is the goal of care to keep the patient alert while treating the underlying cause. Unless the patient has low blood pressure, avoid injecting an entire ampoule (0.4 mg/mL) of naloxone all at once, as it will likely precipitate an acute withdrawal reaction. Instead dilute 0.4 mg of naloxone with 9 mL of normal saline, giving a final concentration of 0.04 mg/mL. Administer 1 to 2 mL (0.04 to 0.08 mg) of the mixture intravenously every 1 to 2 minutes until the blood pressure is normalized. As the effective plasma half-life is short (10 to 15 min due to its high affinity for lipids), monitor the patient every few minutes for recurrent drowsiness. If drowsiness recurs, repeat dosing as required until the patient is no longer compromised.

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Addiction, Pseudoaddiction, Tolerance, and Dependence

The perception that the administration of opioid analgesics for cancer pain management causes addiction is a myth that stands in the way of adequate pain control. Part of the problem is that there is confusion about the differences among addiction, pseudoaddiction, pharmacologic tolerance, and physical dependence. Opioids can be slowly discontinued, even if physical dependence occurs.

Opioid addiction is a complex psychiatric phenomenon that is characterized by compulsive use of an opioid despite harm. The opioid addict is excessively focused on acquiring and using the drug, and other aspects of life suffer such as loss of job, loss of health, and loss of significant relationships.

Opioid pseudoaddiction is an iatrogenic syndrome from pain that is undertreated. Patients with unrelieved pain may become focused on obtaining medications, may clock watch, and may otherwise seem inappropriately drug seeking. Even such behaviors as illicit drug use and deception can occur in the patient's efforts to obtain relief. This can be distinguished from true addiction in that the behaviors resolve when the pain is effectively treated. Misunderstanding this phenomenon may lead the clinician to inappropriately stigmatize the patient with the label “addict.”

Pharmacologic tolerance describes the reduced effectiveness of a given dose of medication over time. Pharmacologic tolerance, alone, is not evidence of drug addiction. Tolerance to side effects, with the exception of constipation, is common and is often favorable. Tolerance to analgesia can be seen, in which case switching to a different opioid (opioid rotation) is recommended. Doses may remain stable for long periods if the pain stimulus remains unchanged. When increasing doses are required, consider worsening disease before concluding that the patient has developed pharmacologic tolerance.

Physical dependence is the result of specific drug/receptor interactions. A characteristic abstinence syndrome signifies physical dependence. Abstinence phenomena are common and are easily managed in standard medicine (β-blockers, estrogen, corticosteroids, etc). In summary, when there is physical dependence, a drug should be tapered, not stopped abruptly. The same rule applies to opioids. Abrupt opioid withdrawal may result in an abstinence syndrome characterized by tachycardia, hypertension, diaphoresis, nausea and vomiting, diarrhea, body aches, abdominal pain, psychosis, and/or hallucinations, but it is not life threatening. Physical dependence is not the same as addiction and is not evidence of addiction alone.

For a patient with cancer pain, if the pain is improved (the cancer gets better) opioid doses usually can be reduced in decrements of 25% to 50% or more every 3 to 5 days, and finally stopped. If the dose is lowered too quickly and abstinence symptoms occur, a transient increase in the opioid dose is all that is needed. For most patients, if their cancer is improved by chemotherapy or radiotherapy, they stop their opioids themselves. When they complain of myalgias, arthralgias, nausea, vomiting, and diarrhea, the common mistake is to diagnose a viral syndrome, instead of opioid withdrawal syndrome. Counsel the patients to taper their opioids instead.

Educate patients, families, and other professionals about the inappropriate fear of addiction when prescribing opioids for cancer pain.

* Opioids by themselves do not cause the psychological dependence of addiction.

* Addiction is a rare outcome of pain management when there is no history of substance abuse.

* As patients with histories of substance abuse can also develop significant pain, they deserve compassionate treatment of their pain when it occurs, and expert help is advised.

Cited By:

This article has been cited 1 time(s).

Pain
Suppression of KCNQ/M (Kv7) potassium channels in dorsal root ganglion neurons contributes to the development of bone cancer pain in a rat model
Zheng, Q; Fang, D; Liu, M; Cai, J; Wan, Y; Han, JS; Xing, GG
Pain, 154(3): 434-448.
10.1016/j.pain.2012.12.005
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Keywords:

cancer; pain; pathophysiology of pain; pain management

© 2011 Lippincott Williams & Wilkins, Inc.

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