Drug Therapy of Pain in Cancer Patients

Paul A. Glare

Cancer Pain Management and Choice of Drugs

Epidemiology of Pain in Patients with Cancer

Pain is one of the most feared consequences of cancer. However, approximately one third of patients with advanced cancer never experience any pain. The incidence of pain varies with the primary site, affecting more than 80% patient with primary tumors of bone, cervix, or head and neck, but less than 20% patients with leukemia or lymphoma.¹ Before diagnosis, cancer patients often present with pain that then resolves with treatment.

Approximately one third of ambulatory patients with cancer on chemotherapy have pain.², ³ Two thirds of patients with advanced cancer have pain, and up to 90% of patients with terminal cancer have pain.¹ Pain is also noted in about one third of cancer survivors. Cancer pain is not a single entity. Patients with cancer often have multiple concurrent pains; in one survey of patients with advanced cancer, 20% had only one pain, while one-third had four or more pains.⁴

There are many ways to classify these various cancer pains and this determines the optimal treatment. One classification is based on etiology: pain may be due to the tumor, may be a side effect of cancer treatments, including the newer targeted therapies, may be secondary to cancer-related debility, or may be secondary to some unrelated painful comorbidity. The prevalence of each depends on the setting (Table 37-1).⁵, ⁶

A second classification of cancer pain, by onset/duration, divides it into acute pain and chronic pain. Most pain due to the tumor is chronic; acute pain in the cancer patient is typically secondary to diagnostic procedures (e.g., bone marrow biopsy, post-LP headache), therapeutic interventions (e.g., mucositis pain, postsurgical pain), or a cancer-associated complication (e.g., DVT, pulmonary embolus). Most of these acute pains are transient and predictable. The key to cancer pain assessment is to identify the underlying mechanism. Lists of acute and chronic cancer pain syndromes have been developed. This simple acute/chronic dichotomy can be problematic in practice. Some neoplasm-related pain can have an acute onset (e.g., pathological fracture of a vertebra) but then persists unless effective treatment of the underlying lesion is provided. Many people with chronic cancer-related pain also experience intermittent, acute flares of pain that can occur even though they are taking analgesic medications on a fixed schedule for pain control. These flares of pain are called breakthrough pain (BTP) because the pain “breaks through” the regular pain medication. Depending on the setting (ambulatory advanced cancer through hospice), approximately one half to two thirds of patients with chronic cancer-related pain also experience episodes of BTP.⁷, ⁸ BTP is serious because it is associated with more severe and frequent background pain, more pain-related functional impairment, and worse mood. BTP is of two types: incident pain, which breaks through otherwise adequate analgesia during the dosing interval, and end-of-dosage failure pain, that emerges toward the end of the dosing interval. Incident pain can be frequent or rare and can be predictable or unpredictable. It is usually somatic but can also be visceral or neuropathic. Dosage failure pain is usually consistent and predictable.

TABLE 37.1 Prevalence of cancer pain by etiology, in different settings⁵, ⁶

Setting	Tumor related (%)	Treatment related (%)	Debility related (%)	Unrelated (%)
MSKCC outpatient, 1989⁵	62	25	—	10
MSKCC outpatient, 2009	67	20	5	10
MSKCC hospitalized, 1989⁵	78	19	—	3
British inpatient hospice⁶	67	5	6	22

Lastly, pain in cancer pain can be classified according to its pathophysiology; cancer pain shares many neuropathophysiological pathways with noncancer pain. Traditionally, this classification has incorporated nociceptive pain (normal transmission of
noxious stimuli from the periphery to the brain via an intact nervous system), neuropathic pain (pain arising from nerve damage in the absence of a peripheral noxious stimulus), and idiopathic pain (no noxious stimulus, intact nervous system).⁹, ¹⁰ The central nervous system (CNS) may also contribute. For example, nociceptive pain due to peripheral inflammation can develop a central neuropathic component due to changes in the dorsal horn of the spinal cord.¹¹ Also, cancer has unique pain states not seen in noncancer pain (e.g., cancer-induced bone pain, cancer- and chemotherapy-induced peripheral neuropathy)¹², ¹³, ¹⁴ that have therapeutic implications.

Assessment of Pain in the Cancer Patient

A comprehensive assessment of the patient is the key to the optimal treatment of cancer pain, aiming to identify the underlying pain mechanism (in effect combining all three of the classifications above) and the psychosocial factors that are influencing the pain experience. Poor assessment has been identified as the principal barrier to effective pain management.¹⁵ However, it may take an extended period of time to determine the precise cause of the pain, as more information about the patient and his/her disease comes to light. Analgesia should not be withheld during the assessment. Alleviating pain is a dominant priority in medical care and will make investigation of the cause of the pain easier. An eight-step approach is advocated (Table 37-2):¹⁶

The clinician must ask the patient if he or she is in pain and use the patient self-report of severity as the guide to treatment; absence of altered vital signs or behavior should not be used as indicator that the patient’s pain reports are false, either in children or adults.¹⁷
The detailed pain history should include onset and temporal pattern, location, description, intensity, aggravating and relieving factors, and impact on function and should include efficacy of any previous treatments. The description is important as the quality of the pain is used to determine the type of pain, for example, burning, shooting, and tingling indicating neuropathic.¹⁸ Ideally, a pain assessment tool such as numerical rating scale or even the Brief Pain Inventory should be used.¹⁹ Electronic symptom assessment tools are becoming available.
A history of substance abuse is becoming increasingly relevant, especially in cancer survivors.
The painful area should be carefully examined to determine if palpation or manipulation of the site produces pain. The neurological aspect of the physical examination is emphasized so that syndromes such as spinal cord compression or base of skull metastases are not overlooked.¹⁸ Common sites of pain referral (e.g. shoulder pain from subdiaphragmatic lesions) should be kept in mind when performing the examination.
Appropriate diagnostic tests should be performed to determine the cause of pain and extent of disease and to correlate this information with the findings on the history and physical exam to ensure that the appropriate areas of the body have been imaged and that the abnormalities found explain the patient’s pain. As pain may be the harbinger of tumor progression, imaging may need to be repeated.
The clinician needs to be familiar with the common cancer pain syndromes (e.g. epidural disease, plexopathies) in order to facilitate identification of the cause so that treatment can be initiated and morbidity (e.g. paraplegia due to cord compression) prevented or minimized. As identifying a treatable cause is only relevant in patients amenable to further anticancer therapy, investigations may be less appropriate in patients with far advanced cancer on hospice or best supportive care.
Unlike the chronic nonmalignant pain patient, a physical basis for pain can usually be identified in the cancer patient. However, anxiety, depression, and other distress are more common in cancer patients than in the general population, so the psychosocial assessment is very important and should emphasize the effect of pain on patient, the family, and any caregiver and should address cognitive, meaning and social aspects of the pain. Identify pathological anxiety or depression that requires specific treatment. Extreme suffering and anguish may present as uncontrollable pain; a “narrative” approach to the cancer pain history will enable the physician to better understand the link between nociception, pain behavior and coping styles, and suffering in the individual patient.²⁰
Subsequent assessment is also required and should evaluate the effectiveness of management. If pain is unrelieved, determine whether the cause is related to the progression of disease, a new cause of pain, or inadequate treatment. These eight steps of the “initial” assessment should be repeated with each new report of pain.

TABLE 37.2 Eight-step approach to cancer pain management

1.	Believe the patient’s pain complaints
2.	Take a detailed pain history and assess the severity of the pain
3.	Include a substance abuse history
4.	Perform a careful physical examination
5.	Order and personally review any diagnostic tests
6.	Consider pharmacological and nonpharmacological approaches to pain syndromes
7.	Assess the psychological state of the patient
8.	Assess the level of pain control afterward

The assessment of BTP requires specific mention. The characteristics of BTP vary from person to person, including the duration of the breakthrough episode and possible causes. Generally, BTP is transient, lasting seconds to minutes, but may occasionally be present for hours, and often occurs several times a day. BTP can happen unexpectedly for no obvious reason, or it may be triggered by a specific activity, like coughing, moving, or going to the bathroom. Importantly, the cause of the BTP may not be the same as that of the baseline chronic pain. For all these reasons, BTP needs as thorough clinical evaluation (proportional to prognosis) as the baseline pain it relates to: site, radiation, intensity, aggravating/relieving factors; physical exam; and investigations. Pharmacological management is the mainstay of treatment, but as this usually involves taking stronger opioids often on multiple times throughout out the day, the inconvenience and toxicity of extra doses suggest that treatment of the underlying cause (e.g., radiotherapy, surgery) should be aggressively pursued, if the treatment is available and the prognosis is appropriate.

Initiating Treatment: The WHO Ladder and the Correct Use of Morphine

Having identified the cause of the pain and the psychosocial factors contributing to the pain-related distress and behavior, individualized multimodal treatment can be instituted. In some cases, anticancer therapy (surgery, radiation, or chemotherapy) can be applied, with either curative or palliative intent, to remove the noxious stimulus and eliminate the pain. However, in many cases, pain is due to advanced, progressive disease and no further treatment options are available; provision of analgesia becomes the main focus of treatment. Even if anticancer treatment is available, analgesia should be provided while it is being scheduled and taking effect. Delivery of effective anticancer therapy can be interfered with when the patient is in pain. The use of anticancer therapy does not preclude the use of analgesics.

Analgesic drugs are the mainstay of cancer pain treatment and fall into three groups, the nonopioids—aspirin, acetaminophen, or nonsteroidal anti-inflammatory drugs (NSAIDs), the weak opioids, and the strong opioids. Coanalgesic drugs are often used as opioid-sparing agents to reduce toxicity or when pain is incompletely responsive to single-agent opioids. The sequential use of analgesics of increasing potency according to the severity of the pain was proposed in the early 1980s by the World Health Organization (WHO)¹⁶ and is often referred to as the WHO Analgesic Ladder. According to these guidelines, a trial of opioid therapy should be given to all cancer patients with pain of moderate or greater severity. Some 30 years on, authorities continue to widely endorse the guiding principle behind the ladder, that analgesic selection should be primarily determined by the severity of the pain.²¹, ²², ²³, ²⁴ But the ladder is not without its critics; a systematic review has criticized the evidence for the efficacy of the ladder.²⁵ The eight studies included in the review were case series,²⁶, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³², ³³ precluding meta-analysis. While each study claimed efficacy of greater than 70%, numerous methodological problems were noted including no information on conditions in which the pain was assessed; two were retrospective; two had short or variable follow-up periods; and three had high withdrawal rates. The review concluded that the evidence provided was insufficient to estimate the efficacy of the ladder. Another study has also challenged the efficacy of the ladder.³⁴

Current cancer pain guidelines recommend that patients with mild pain should receive an NSAID or acetaminophen.²²,³⁵ The choice of drug is based on a risk/benefit analysis for individual patients. Much of the evidence for NSAIDs comes from the noncancer pain literature. A systematic review of the safety and efficacy of NSAIDs in cancer pain included 25 studies of both single and repeated dosing of various agents.³⁶ Single-dose studies found NSAIDs to be roughly equivalent to 5 to 10 mg IM morphine. Some evidence suggested a dose-response effect with a ceiling effect to analgesia. A lack of comparable studies precluded testing whether NSAIDs are particularly effective for malignant bone pain.

Weak opioids (e.g., codeine, hydrocodone, tramadol, propoxyphene) are recommended by the WHO Ladder for moderately severe pain, or mild pain persisting despite treatment with a nonopioid. However, the need for weak opioids is controversial as low dose formulations of strong opioids have been used for the management of mild-moderate pain and may be more effective than weak opioids.³⁴ Consequently, many experts now advocate skipping the second step of the Ladder and using strong opioids for all cancer pain of moderate intensity or greater.²¹,²³,³⁷, ³⁸ Whether weak opioids alone or in combination with nonopioids are more effective than nonopioids alone has also been controversial. While the efficacy achieved by single doses of weak opioids such as codeine is poor, multiple doses may perform better. At therapeutic doses, no evidence suggests that one opioid is better than another for mild to moderate pain.³⁹ Tramadol is an opioid with additional effects on the monoaminergic system.⁴⁰ At therapeutic doses, its analgesic effect is similar to that of an opioid for mild to moderate pain in combination with a nonopioid.⁴¹, ⁴² The extent to which the dose can be titrated is limited; at doses just above the normal therapeutic dose, tramadol can cause convulsions and it produces serious psychiatric reactions at therapeutic doses in some patients.⁴⁰ For these reasons, tramadol offers little advantage over other opioids for mild to moderate pain in patients with advanced cancer.

Meperidine, once the opioid of choice for many physicians, has no place in the modern management of cancer pain. It is no more effective than morphine at treating biliary or renal pain, and its low potency, short duration of action, and unique toxicity (i.e., seizures, delirium, other neuropsychological effects) relative to other available opioid analgesics have led to its declining use. Several countries, including Australia, have put severe limits on its use or curtailed it outright. Nevertheless, some physicians continue to use it as a first-line analgesic, and it is found on the WHO Essential Drug list.

Strong opioids are the mainstay of the management of moderate to severe cancer pain. While opioids have been used as analgesics for centuries, it is only recently that a systematic review has concluded that oral morphine is effective for cancer pain.⁴³ Although numerous strong opioids are FDA-approved for cancer pain management, morphine remains the drug of first choice,²¹ for the following reasons:

the majority of patients tolerate morphine well
it is usually effective, dose titration to a suitable level of analgesia usually being achievable
for long-term use, the oral route is preferable to parenteral or rectal
a wide variety of oral formulations are available, allowing flexibility of dosing intervals
other opioids have less long-term safety data.

Alternative opioids such as hydromorphone, oxycodone, fentanyl, methadone, oxymorphone, and levorphanol should be used when titration of morphine results in dose-limiting side effects.

The principles for the correct use of morphine are shown in Table 37-3 and are based on published guidelines.²¹,⁴⁴ Studies in the 1970s showed that oral morphine was as effective as parenteral morphine, but more had to be given (approximately triple the intravenous [IV] dose with repeated administration) because it undergoes extensive first-pass hepatic metabolism. In patients with chronic cancer pain, oral morphine should be given on a regular scheduled basis, around the clock, to keep pain under control and prevent peaks and troughs in blood levels. The starting dose of oral morphine depends on whether or not the patient was opioid naïve or
progressing from a weak opioid. Naïve patients should be started on 5 mg of immediate release (IR) morphine and tolerant patients on 10 mg, given q4h plus PRN (as necessary). The dose is titrated up in 50% to 100% increments every 12 to 24 hours until the pain is controlled. Using this approach, respiratory depression and excessive sedation almost never occur. Once the pain is controlled, the patient should be converted to a sustained release (SR) formulation to improve adherence (calculate total daily dose with IR, divide by two, and administer as SR bid; a supply of IR needs to be available for rescue dosing in cases of BTP). The rescue dose for oral pain medicines is usually one twelfth to one sixth of the total daily dose. It is important to anticipate the common side effects of morphine, especially constipation, and prescribe prophylactic laxatives. Nausea is less common and usually self-limiting; prophylactic antiemetics are not usually needed.

TABLE 37.3 Ten principles for the correct use of morphine in chronic cancer pain

1.	Administer by mouth
2.	Administer around the clock not PRN
3.	Start immediate-release morphine and titrate up dose
4.	Change to sustained-release morphine when dose is stable
5.	Continue immediate-release morphine for rescue dosing (breakthrough pain)
6.	Anticipate and prevent side effects, especially constipation
7.	Know that the oral:parenteral equipotency ratio is 3:1
8.	Reduce dose in renal failure because of accumulation of the active metabolite morphine-6-glucuronide
9.	Know how and when to use opioid rotation
10.	Educate patient and family about morphine

TABLE 37.4 Opioid equianalgesic table

Drug	IV	PO	Duration	Comment
Morphine	10	30-60	3-4 h	Standard for comparison; Multiple routes available
Hydromorphone	1.5	7.5	3-4 h	Multiple routes; available in HP form (10 mg/mL)
Oxycodone	—	30	3-4 h	Often 5 mg combined with ASA or acetaminophen; long-acting available; short-acting comes in tablet or elixir
Fentanyl	^b	^b	^b
Methadone^a	10	20	6-8 h	May accumulate due to long half-life and result in delayed toxicities. Carefully monitor during titration
Oxymorphone	1	10(PR)	3-4 h
Levorphanol^a	2	4	4-6 h	May accumulate due to long half-life and result in delayed toxicities during initial dosing or increased dosing
Codeine	130	200	3-4 h	Metabolized to morphine; often combined with acetaminophen
Hydrocodone	—	30	3-4 h	Oral formulation only in combination with acetaminophen
Equivalency of various opioid analgesics to 10 mg of IV morphine
^aDue to the long half-life, much lower doses will be needed for ATC dosing. ^bFentanyl 100 μg/h (IV or TD) is equivalent to MS 4 mg IV/h or PO MS 200 mg/24h.

The SR morphine dose needs to be reviewed regularly and may need titration upward if progression of disease is causing increasing pain. In some patients, the noxious stimulus is eliminated in which case the dose needs to be reduced,⁴⁵, ⁴⁶ tapering by 25% to 50% or less, every 2 to 3 days. When tapering, educate the patient about possible withdrawal symptoms and give suggestions for abating those symptoms. The dose also needs to be reduced if renal failure occurs, as the active metabolite, morphine-6-glucuronide, accumulates (presenting with respiratory depression and/or neurotoxicity: drowsiness, confusion, myoclonic twitching).⁴⁷, ⁴⁸ It is recommended that morphine and codeine are avoided in renal failure/dialysis patients; hydromorphone or oxycodone are used with caution and close monitoring; and that methadone and fentanyl/sufentanil appear to be safe to use.⁴⁹ The “safe” drugs in renal failure are also the least dialyzable.

If patients develop dose-limiting side effects, rotation to another strong opioid may enable a dose increase because of interindividual variation in side effects for the various opioids. On making the switch, the opioid dose may need to be decreased because cross-tolerance between the opioids is limited (see Section on “Opioid Rotation”). It is important to know the relative potency ratios of the alternatives to morphine—all are more potent, between 1.5 and 100 times (see Table 37-4).⁵⁰ Cost issues are also pertinent as patients may not have insurance coverage for them.

In many patients with advanced cancer, parenteral opioids are needed at some stage in the course of their illness, either because of a pain crisis or because they are unable to swallow. If patients are hospitalized, the IV route is used; in hospice patients, the subcutaneous (SC) route is used. IM injections should be avoided.
In up to 10% patients, the spinal route is indicated.⁵¹ Finally, when initiating morphine, patients and families must be educated about the patient-related barriers to taking strong opioids—side effects, stigma, tolerance, addiction, and approaching death.⁵²

Intravenous Morphine

IV morphine is usually given by continuous infusion, with rescue doses administered on demand by clinicians (clinician activated bolus or CAB) or self-administered by the patient (PCA or patient controlled analgesia). Hospitals have IV therapy guidelines to prescribe and administer IV opioids. Generally, morphine sulfate and hydromorphone can run simultaneously with other solutions, including antibiotics; this is not the case with fentanyl and methadone. A separate line is required for fentanyl and methadone.

If the patient requires admission to hospital with a pain crisis, IV PCA is preferred. Guidelines suggest an increase of 25% for mild-mod pain and an increase of 50% for mod-severe pain, but the increase should be based on the number of rescues taken. When converting from oral to IV, the IV dose is reduced to one third of the oral dose, expressed as an hourly rate (e.g., 30 mg oral morphine q4h becomes 2.5 mg IV morphine/h). Start with an IV rescue dose of half hourly IV basal q15-20 minutes or an oral rescue of 10% to 15% of the total daily opioid dose q1-2h. In managing a pain crisis in an opioid-tolerant patient, double the IV dose is administered as a bolus, repeating same dose in 20 minutes if no relief. If the pain persists at a level greater than six-tenth, with no side effects, increase the IV dose by 50% and continue to administer a dose every 20 minutes until benefit or side effects are seen. Once relief is obtained and PCA is to be started, the total amount of opioid the patient used in the past 24 hours is converted into an IV dose equivalent for the past 24 hour and converted into an hourly dose for the PCA basal rate, then rescues are ordered. For opioid-naïve patients in a pain crisis, morphine sulfate is given in 5 to 15 mg IV boluses until relieved and the starting basal rate for PCA is 1 to 3 mg/h.

When utilizing PCA, patient care staff members need individual instruction on how to access the readings on the PCA pump and perform other functions. PCA is contraindicated in patients who are confused. In those cases, the PRN “rescue” button should not be used and can be removed from the pump. Family members should be instructed NOT to push the PRN “rescue” button; only the patient should administer the PRN “rescue” dose. CAB is a larger rescue dose (typically double the hourly rate), only administered by a nurse or physician. CABs are useful to allow patients who cannot tolerate lying down to have an MRI or radiation therapy. CABs can also be used for a pain crisis, severe incidental BTP, or other painful episodes. PCA can be delivered at home with the support of an infusion company.

Opioid Rotation

While morphine works well in the majority of patients, some 10% to 30% patients experience intolerable dose-limiting side effects that prevent titrating it up to the effective dose.⁵³ The strategies available for dealing with this situation include persisting with morphine and managing the side effects with adjuvant medications, for example, antiemetics, psychostimulants, more aggressive laxatives; using coanalgesic drugs that will be opioid sparing, such as NSAIDs in the case of bone pain or antidepressants or anticonvulsants in the case of neuropathic pain; using anesthetic procedures, for example, nerve blocks, or changing to an alternative strong opioid, often referred to as “opioid rotation.”

The underlying premise of opioid rotation is that an alternative opioid may have the same efficacy but a different side effect profile to morphine. However, because all strong opioids are mu opioid agonists, it is unclear how opioid rotation works. Possible mechanisms include genetic factors (e.g., differences in drug metabolism), drug factors (differences in structural formula and opioid binding, binding to mu opioid receptor subtypes, non-mu opioid receptor binding, activation of secondary messenger systems, metabolic pathways, and nonopioid activity (e.g., N-methyl D-aspartate [NMDA] receptors in the case of methadone), and environmental factors (e.g., drug interactions). The effectiveness of rotation is unproven; the few well-designed studies of randomized initiation of opioid therapy have found no significant difference between agents.⁵⁴ All opioids have similar adverse effect profiles when given in equianalgesic doses. Nevertheless, a large body of anecdotal evidence supports its efficacy, with more than 20 uncontrolled studies indicating efficacy in ≥80% cases.⁵⁵ Opioid rotation is now included in cancer pain guidelines²¹ and is very common, being utilized in more than 70% patients in one series with 20% having two or more rotations.⁵⁶ Not all use of alternative opioids is secondary to dose-limiting side effects. Other reasons include comorbidities (e.g., renal failure), availability of alternate formulations and routes, patient preference, and cost.

Abuse Potential

Abuse of controlled prescription drugs is a serious problem. The presence of pain and a combination of psychological and physiological factors tend to prevent the development of addiction, although physical dependence and tolerance will develop with protracted opioid therapy. The experience at Memorial Sloan-Kettering Cancer Center is that addiction is much less common than in general medical populations.⁵⁷ However abuse may potentially afflict the cancer patient and drug, genetic and environmental factors influence whether or not an individual will abuse drugs. Opioid administration for pain in cancer patients who have no prior history of substance abuse is rarely associated with significant abuse or addiction.³³,⁵⁸

There is increased interest in assessing the abuse liability of prescription opioid products. In a large epidemiological study,⁵⁹ hydrocodone ranked as high as extended release (ER) oxycodone as an abused drug (with all other drugs grouped together at very low levels of abuse) when measured per capita, but buprenorphine products, ER oxycodone, and methadone were the most intensely abused when corrected for the degree of exposure, with hydrocodone ranking as the least abused. Geography matters: In certain very small urban, suburban, and rural areas, disproportionately high levels of abuse were noted relative to therapeutic use (>95th percentile). Abuse liability can also be evaluated according to attractiveness of the drug formulation to the substance abuse population. In a Boston survey of substance abusers, ER oxycodone, hydromorphone, and an oxycodone-acetaminophen combination were ranked
most attractive for abuse, with pentazocine-naloxone combination and transdermal fentanyl being ranked least attractive.⁶⁰ On the other hand, Canadian addicts ranked fentanyl highly, no different than ER oxycodone.⁶¹

Drug-related factors contributing to abuse liability can be intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to it (e.g., availability, availability of alternatives, cost, street value). For example, two studies have demonstrated that for the same unbound opioid concentration in peripheral blood, the concentration of unbound oxycodone in brain is sixfold higher than that of morphine,⁶², ⁶³ which may explain in part the high abuse level of oxycodone.

Pharmacokinetic principles would suggest that short-acting drugs and the parenteral route are more likely to lead to problematic drug behaviors, so long-acting agents should be used whenever possible. An abuse risk exists with all opioids but is particularly high with oxycodone. If concerns about addiction are great for other reasons, it may be prudent to avoid ER oxycodone.

Coanalgesic Agents

“Coanalgesic” is the term used to describe agents given as adjuvants to enhance the pain relief provided by an opioid. The list of potential adjuvants is extensive and can include agents that are primary analgesics in other circumstances (NSAID, acetaminophen). The basis for using coanalgesics is that some types of pain are less responsive to opioids than others, and that much higher doses of opioids—associated with worse side effects—are needed if these pains are managed with “single-agent” analgesics. Neuropathic pain, pain secondary to osseous metastases, and painful muscle spasms are typical examples of pains for which coanalgesics may be helpful. Occasionally, coanalgesics are used as first-line options, for example, for chemotherapy-related peripheral neuropathy. However, in the majority of cancer patients, these pain syndromes usually result from the effects of a tumor mass and an opioid is required.

Neuropathic pain is the commonest example of pains that may require coanalgesics, and the antidepressants or anticonvulsants are the commonest and most effective coanalgesics. Most studies of coanalgesics have been undertaken in nonmalignant pain (diabetic neuropathy and postherpetic neuralgia). It is noteworthy that the number needed to treat (NNT) for the coanalgesics (antidepressants NNT 2-4, anticonvulsants NNT 4-5) is the same as that for opioids (NNT 2-5).⁶⁴ This can be interpreted to mean that the coanalgesics should be tried as first-line options for pure neuropathic pain. It may also be interpreted to mean that addition of these agents may be expected to provide limited improvement in analgesia in patients responding suboptimally to opioids. Prescribing coanalgesic drugs contributes to polypharmacy with its attendant problems of drug interactions, toxicity, inconvenience, and cost. It used to be taught that the neuropathic pain descriptors directed coanalgesic choice—antidepressants for burning deafferentation-type pain, anticonvulsants for shooting/lancinating neuralgic-type pain—but this distinction no longer appears to be clinically relevant. Choice of drug will be dictated by toxicity, drug interactions, and coexisting conditions.

Among the antidepressants, the tricyclic antidepressants (TCAs) are the most extensively studied and are effective (NNT 2-3) but they have common side effects and are especially poorly tolerated by the elderly. Most of the common serotonin reuptake inhibitors, such as escitalopram, are not effective as coanalgesics, but serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine are effective although less so than TCA (with NNT around 5). Gabapentin and pregabalin are the main two anticonvulsants used in cancer patients because of their superior side effect and drug interaction profile when compared to carbamazepine. Carbamazepine is a strong inducer of CYP 3A4 P-450 and may cause blood dyscrasias; it should probably be avoided in cancer patients. Gabapentin and pregabalin may be slightly less effective (NNT 4-5) than the antidepressants but are usually better tolerated; drowsiness, dizziness, and pedal edema are the main side effects. Both work via the same mechanism of action, but pregabalin has some advantages over gabapentin, including linear pharmacokinetics, faster time to effective dose, and bid dosing. Topical lidocaine 5% patches (applied for up to 12 hour/d) are FDA approved for postherpetic neuralgia and recommended off-label in cancer pain guidelines for malignant neuropathic pain. They are effective (NNT 4-5), have little toxicity and high acceptability with patients, and are worth trying if the painful area is not too extensive.

NSAIDs block the cyclooxygenases (COXs), which produce prostaglandin E2 (PGE2) from arachidonic acid. PGE2 is implicated in the production of inflammation and pain, by directly stimulating nociceptors and altering the sensitivity of nociceptors to other pain-producing substances, such as bradykinin, released as part of tissue damage caused by tumor. NSAIDs may also have a role in neuropathic pain as PGE2 has a role in central sensitization of nociception in the dorsal horn of the spinal cord.⁶⁵ Two forms of COX exist, and NSAIDS can be divided based on whether they are COX 2 selective or not. COX 2 selective agents may cause fewer gastrointestinal (GI) tract side effects and less renal toxicity than the nonselective NSAIDs but increase the risk of thrombotic events. Toxicities resulted in the removal of all COX 2 selective agents from the market, except celecoxib.⁶⁶

More than 15 NSAIDs are FDA-approved; selection depends on availability, side effects, contraindications, patient preference, fashion, and cost. Unfortunately, NSAIDs are contraindicated in many cancer patients who would otherwise benefit from them because of renal impairment, thrombocytopenia, or risk of bleeding during an invasive procedure. In patients without GI or cardiovascular risk factors, a nonselective NSAID should be used; to reduce toxicity, acidic, short half-life agents such as ibuprofen, diclofenac, and indomethacin are preferred.⁶⁷ In patients with GI or cardiovascular risk factors, a selective agent (celecoxib) should be used,⁶⁷ preferably in low doses.

Acetaminophen is commonly considered together with NSAIDs as a coanalgesic. Although the analgesic potencies of acetaminophen and NSAIDs are comparable, their mechanisms of action are thought to be different. In the United Kingdom and Australia, acetaminophen is frequently added to strong opioids to improve analgesia, but in the United States it is often only used with weak opioids. The rationale for adding acetaminophen to a strong opioid regimen is to improve the balance between analgesia and side effects by either increasing analgesia without adding side effects or by maintaining analgesia with fewer side effects from opioids, NSAIDs, or other drugs. Acetaminophen has been shown to provide improved pain and well-being without major side effects in
patients with cancer and persistent pain even when they are taking strong opioids.⁶⁸ Acetaminophen shares none of the subjective side effects of NSAIDs, opioids, or other coanalgesics. It is usually safe and well tolerated in therapeutic doses. Hepatic toxicity is the only serious complication, but this is rare with doses less than 8 g/d, even in patients with chronic liver disease.

Pharmacology of Drugs Commonly Used for Pain Control in Cancer Patients

The formulations and dosage strengths of opioids are shown in Table 37-5. The main pharmacokinetic parameters of opioids are shown in Table 37-6.

TABLE 37.5 Formulations and dosage strengths of opioids

Morphine
MS Contin	15, 30, 60, 100, 200 mg
MSIR	15, 30 mg
Morphine elixir	20 mg/mL (outside MSK, it also comes in 1 mg/mL)
Avinza capsule	30, 60, 90, 120 mg
Kadian capsule	20, 30, 50, 60,80, 100, 200 mg capsules
Suppository	5, 10, 20, 30 mg
Injectable	multiple; pharmacy has 25 mg:1 and 50 mg:1
	For PCA, use 1:1 or 10:1 concentration (or greater if necessary)
Hydromorphone
Tablets	2, 4, 8 mg (Elixir 1 mg/mL)
Suppository	3 mg
Injectable	2 and 4 mg/mL; 10 mg/mL for pharmacy use
	For PCA, use 1:1 or 10:1 concentration
Oxycodone
OxyContin	10, 20, 40, 80 mg
Oxycodone	tab 5 mg
Oxycodone elixir	1 or 20 mg/mL
Oxymorphone
Opana	5-, 10-mg tablets
Opana ER	5-, 10-, 20-, 40-mg tablets
Opana Injectable	1 mg/mL
Methadone
Tablets	5, 10, 40 mg
Injectable	10 mg/mL
	For PCA, use 1:1 or 10:1 concentration
Fentanyl
Patch	12, 25, 50, 75, 100 μg/h
Injectable	For PCA, use 50:1 (or 10:1 concentration, if very low basal)
Transmucosal
Lozenge	200, 400, 600, 800, 1200, 1600 μg
Tablet	100, 200, 300, 400, 600, 800 μg

Strong Opioids

Morphine

The clinical pharmacology of morphine is discussed in detail because of its status as the preferred strong opioid for cancer pain and because other opioids are semisynthetic or synthetic variations on it, and thus similar in many respects. Morphine is a naturally occurring opium alkaloid from the phenanthrene group.⁶⁹ It is a weak base with a pK_a of 7.9. At a physiological pH, 76% of its molecules are ionized. It has hydroxyl groups at the C3 and C6 positions that make it relatively water soluble and poorly lipid soluble. Morphine is available for therapeutic use as the hydrochloride, sulfate, and tartrate salts, in a wide variety of formulations.

Pharmacodynamics of Morphine

Morphine produces it effects by being an opioid receptor agonist. Its primary affinity is for the mu subclass of receptor expressed mainly in the spinal cord and brain. The receptor is a member of the G-protein coupled receptor superfamily. Morphine also binds the kappa and delta subclasses of opioid receptors with some affinity.⁶⁹ The main responses mediated by activation of the opioid receptors include analgesia, sedation, respiratory depression, emesis, reduced GI motility (leading to nausea and constipation), and changes in mood (euphoria, dysphoria, and psychotomimetic). While analgesia is the principal desirable effect of morphine, it has been used for other medicinal purposes throughout the ages, including as an antidiarrheal agent and an antitussive. It is also used for the relief of breathlessness in both cancer and nonmalignant diseases.⁷⁰

Only gold members can continue reading. Log In or Register to continue