Pain Part 2

Principles of Pain Management

Eleven principles should guide the management of pain [see Table 2].

• Take a detailed history of the patient’s pain (see above). An accurate assessment of the patient’s pain is essential for the direction of future therapy.

• Design a patient-specific diagnostic and therapeutic approach. Although there are numerous guidelines for treatment of pain in different conditions, pain is a complex subjective experience requiring an individualized approach. Management of pain should take into account such factors as the underlying cause (or causes) of pain, medical comorbidities, psychological state, response to prior therapies, functional status, compliance with or tolerance of different therapeutic regimens, and objectives of therapy.

• Ensure the availability of expertise to provide therapeutic alternatives. Pain may be managed in a variety of clinical settings. In a multidisciplinary pain treatment center, expertise on a variety of alternative therapies may be readily available. When primary management of pain occurs in other settings, access to external resources must be assured.

• Choose the simplest approach before attempting more complicated and invasive techniques. As initial therapy of a given painful condition, medical management may be superior to invasive techniques on the basis of risk/benefit assessment, cost, and other factors. For drug treatment, selection of agents can follow the stepwise approach advocated by the World Health Organization (WHO).46

• Maintain ongoing communication between physician and patient in defining therapeutic options and potential risk-to-benefit ratios of each approach. Patients may respond better to therapeutic regimens that they helped to select and in which they therefore feel invested.

• Titrate doses to maximize efficacy and minimize side effects. Inadequate dosing of analgesics may be the most frequent cause of undertreatment of pain. To provide optimal pain management, physicians require training in proper dosing of pain medications, guidelines for dose titration, and significant side effects of pharmacologic agents (see below). Optimal titra-tion will vary between patients. Physicians who adhere to accepted management guidelines need not fear legal or professional repercussions from their treatment of patients in pain.

• Anticipate and treat side effects. Poor management of side effects is associated with suboptimal treatment compliance, leading to continued pain and such secondary pain-related problems as mood disturbance, inactivity, and impaired function.

• Utilize adjuvant medications for analgesia and for specific pain syndromes. Specific painful conditions may best be treated with multiple analgesics. Adjuvant medications should be employed when clinical evidence supports their use.

• Distinguish physical dependence from psychological dependence. Surveillance for and prevention of psychological dependence (i.e., addiction) is a legitimate concern when opiates are used for pain management. Nevertheless, excessive fear of addiction is a significant barrier to optimal pain management. Patient (and physician) fears and misconceptions should be dealt with in frank discussion. Patients must be counseled that in the absence of a history of substance abuse, the likelihood of developing addiction while taking opioid medications for pain has proved exceedingly rare (occurring in less than 1% of patients in many studies).47 Physical dependence, a common phenomenon, must be defined and differentiated from addiction. Especially with new patients, it is important for physicians to be familiar with the diagnostic criteria for substance abuse disorders; these disorders present a different set of management problems [see 13:Vl Drug Abuse and Addiction].

• Provide continuity of care throughout evaluation and treatment. Fragmentation of care is a significant contributor to the suboptimal medical treatment often received by patients with chronic or complex pain. Failure to establish a durable physician-patient relationship may lead to the incorrect perception of so-called doctor-shopping and drug-seeking behavior by a patient who lacks a coordinated pain management strategy. Involvement of numerous providers in the pain management process may predispose to such fragmentation.

• Continually reassess the degree of pain relief and the impact of treatment on mood, function, and overall quality of life. Ongoing assessment of the degree to which treatment goals are being met allows for appropriate adjustment of the therapeutic regimen. Reassessment is especially critical after changes in pharmacologic agent or dosing, as well as after nonphar-macologic interventions. Much of the clinical import of pain relates to its impact on mood, function, and quality of life; assessment of the effect of therapy on these secondary variables is of special significance. Assessment of ongoing patient pain complaints may also be a valuable part of monitoring underlying disease processes.

The frequency of pain reassessment should be keyed to the nature of the pain. Reevaluation of acute pain is usually done after therapeutic interventions over a short time frame. Reassessment of chronic pain is more likely to occur at predetermined intervals over an extended period. Frequency will also vary with clinical setting. For example, inpatients and long-term care residents may undergo pain assessment as the so-called fifth vital sign on nursing rounds, whereas outpatients may have follow-up as appropriate. The specific tools with which pain is reassessed will vary with patients as necessary.

Management of Pain in Specific Conditions

Cancer

Most pain in patients with advanced cancer is caused by the cancer itself (e.g., tumor growth leading to tissue invasion, painful metastases, or involvement of the nervous system or visceral structures).35 Therefore, treatment of the underlying malignancy with chemotherapy, radiotherapy, or surgery is a vital component of the management of cancer pain. However, symptomatic relief is often necessary as well, which is commonly achieved with drug therapy.

The WHO’s three-step analgesic ladder can be used to guide the selection of pain medication [see Figure 3].’48 In validation studies, the WHO ladder was found to be effective in 69% to 100% of adults with cancer.48-50 In step one, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are used for patients with mild pain. If the pain persists or increases (i.e., becomes moderate pain), treatment progresses to step two, in which nonopioids are combined with opioids such as codeine and hydrocodone or are given in the form of combination analgesics such as oxycodone with acetaminophen. For severe pain, treatment progresses to step three, which involves opioids with higher potency (e.g., morphine, methadone, hydromorphone, or fentanyl), with or without nonopioids. Adjuvant drugs may be utilized at any level of the ladder. Common adjuvants include corticosteroids (the most widely used agents for this purpose); antidepressants, anticonvulsants, and other agents for neuropathic pain; bisphosphonates and radionuclides for bone pain; and antibiotics for pain from ulcerating tumors. Nonpharmaco-logic adjuvant treatments such as external-beam radiation, neu-rosurgical ablative procedures, psychiatric therapy, and anesthetic interventions may also be employed. Management of cancer pain may be complicated significantly by the simultaneous need to manage multiple other symptoms of advancing malignancy, including fatigue, depression, dyspnea, anorexia, cachex-ia, chronic nausea, and anxiety.

Table 2 Principles of Pain Management

1. Take a detailed history of the patient’s pain

2. Individualize the therapeutic approach

3. Ensure the availability of expertise to provide therapeutic alternatives

4. Choose the simplest approach before more complicated and invasive techniques 5. Maintain ongoing communication between physician and patient in defining therapeutic options and potential risk-to-benefit ratios of each approach

6. Titrate doses to maximize efficacy and minimize side effects

7. Anticipate and treat side effects

8. Utilize adjuvant medications for analgesia and in specific pain syndromes

9. Distinguish physical dependence from psychological dependence

10. Provide continuity of care throughout evaluation and treatment

11. Continually reassess the degree of pain relief and the impact of treatment on mood, function, and overall quality of life

HIV/aids

The increasing life expectancy of patients with HIV infection has led to the characterization of HIV/AIDS-related pain as a type of chronic pain. Management of pain in this setting is complicated greatly by the diversity of pathologic mechanisms un-derlying the variety of pains and pain syndromes seen in these patients. The Agency for Healthcare Policy and Research (AHCPR) recommends that the WHO approach to cancer pain management (see above) be used for the treatment of painful conditions in HIV/AIDS patients.

Figure 3 The World Heath Organization’s three-step analgesic ladder can be used to guide the selection of pain medication.

It has been suggested that as many as 85% of patients with HIV/AIDS-related pain do not receive adequate pain treatment. Women, substance abusers, and patients of low socioeconomic status are particularly vulnerable.51

Pharmacologic Management of Pain

The WHO, the American Pain Society, and the AHCPR have published specific guidelines on analgesic use.45,47,52 Although the WHO analgesic ladder (see above) provides a useful construct for drug selection, pharmacotherapy ultimately must be tailored to the individual patient, taking into account the patient’s medical comorbidities, response to prescribed drugs, side effects experienced, and a wide range of psychosocial and quality-of-life variables.

Opioid analgesics

Indications

Opioids play a significant role in the treatment of a number of conditions, including acute pain, trauma-related pain, postoperative pain, cancer pain, and some types of chronic noncancer pain, including osteoarthritis, low back pain, and neuropathic pain. Because responsiveness to opioids varies between patients, failure of response to an adequate trial of one opioid should be followed by an adequate trial of another opioid. Within a given potency range, there is little evidence to recommend one opioid over another as the initial prescribed agent. Selection of initial analgesic agent often is based on a combination of drug characteristics (e.g., half-life and duration of effect, speed of onset, route of administration) and patient characteristics (e.g., prior response to different opioids) [see Tables 3 and 4].

Neuropathic pain The role of opioids in neuropathic pain has been established since the late 1990s, when a series of well-designed randomized controlled clinical trials clearly demonstrated efficacy in neuropathic pain states such as diabetic neuropathy. Current data suggest that neuropathic pain may be managed more effectively when morphine is combined with gabapentin than when either agent is used alone [see Antiepilep-tic Drugs, below]. Although monotherapy is often tried initially in managing neuropathic pain (most commonly with gabapentin), many patients are best served by a so-called cocktail approach that targets multiple mechanisms.

Table 3 Opioid Analgesics Used for Mild to Moderate Pain

Drug	Dosage (Oral)*	Analgesic Equivalence (mg)f	Duration
Codeine	15-60 mg q. 4 hr	200	3-4 hr
Hydrocodone	5-15 mg q. 4-6 hr	200*	3-5 hr
Meperidine	50-150 mg q. 3-4 hr	300	2-3 hr
Propoxyphene	65 mg q. 4 hr	200	3-6 hr

*These agents are typically combined with acetaminophen or aspirin, which limits dose escalation.

+Compared with 30 mg of oral morphine.

{Equivalence unsubstantiated but thought to approximate codeine.

Mechanism

Opioids achieve their analgesic effects chiefly by interacting with opioid receptors in the CNS. This binding inhibits the transmission of nociceptive impulses from periphery to spinal cord, activates descending pain suppression pathways, and modulates activity in the limbic system. Pain relief from opioids may also derive in smaller part from activity at receptors in the peripheral nervous system. Individual opioids display different affinities for, and interactions with, each of the three types of opi-oid receptors (mu, kappa, and delta; see above). Many of the most commonly used opioids are mu agonists. Differences in binding patterns underlie many of the differences in side effect profile among individual agents. Although opioid receptors are found primarily in the CNS and the gastrointestinal tract, they are widely distributed throughout the body; the potential analgesic significance of receptor networks outside the CNS is not fully understood at present.

Table 4 Opioid Analgesics Commonly Used for Moderate to Severe Pain

Drug	Dose	Half-life (hr)	Comment
Morphine	10 mg I.V., 30 mg p.o.	2-4	Standard of comparison for opioid analgesics; start with a lower dose in patients with respiratory insufficiency, increased intracranial pressure, liver failure, or renal failure
Hydromorphone	1.5 mg I.V. , 7.5 mg p.o.	2-3	Slightly shorter acting
Methadone	10 mg I.V., 20 mg p.o.	15-20	Good oral potency; long plasma half-life, so repetitive dosing may result in accumulation and excessive sedation
Fentanyl	100 ^g = 4 mg I.V. morphine	1-2	Short half-life; transdermal and transmucosal preparations available
Meperidine	75 mg I.V., 300 mg p.o.	2-3	Not recommended for patients with chronic cancer pain or impaired renal function or those receiving monoamine oxidase inhibitors
Levorphanol tartrate	2 mg I.V., 4 mg p.o.	12-16	—
Oxycodone	30 mg p.o.	3-4	Typically used in combination with nonopioid analgesics that limit dose escalation
Oxymorphone	1 mg I.V., 6 mg p.r.	2-3	Not available orally

Administration and Formulation

Opioids may be administered via a wide range of routes— oral, sublingual, rectal, intravenous, transdermal, intrathecal, epidermal, and subcutaneous. The preferred mode of administration will vary with the specific opioid, the severity of pain, and the patient’s medical condition. Not all opioids are available in all dosing forms. The oral route is usually used for systemic administration. For mild to moderate pain, there is no consistent evidence that any route of systemic administration is superior to oral administration; other systemic routes may be preferred for more severe pain. Oral or transdermal administration generally is preferred for treatment of chronic conditions. Medical factors may prevent oral administration. For example, patients with end-stage dementia often lose the ability to swallow medications, and 80% of cancer patients are unable to take oral opioids for some time before death, because of intractable nausea, oral mucositis, dysphagia or aspiration concerns, bowel obstruction, or other conditions. Oral administration may be impractical for very high dose opioid therapy because the patient would have to swallow an unreasonable number of tablets.

Intravenous opioid administration has a number of other advantages. Intravenous administration provides rapid onset of effect and allows rapid titration to optimal analgesia. Avoidance of first-pass hepatic degradation yields higher bioavailability and thus an opportunity to reduce total dosage. Continuous intravenous administration may provide the patient with a consistent level of analgesia. However, the greater potency of intravenous opioids increases the risk of systemic side effects, particularly if rapid dose escalation occurs or if the patient is opioid naive.

Subcutaneous injection may be used when small fluid volumes are sufficient to deliver the prescribed opioid dose. This route enables rapid titration and onset of analgesia; however, a shortened duration of effect necessitates frequent redosing to maintain constant pain relief. The risk of side effects is greater with subcutaneous than with oral administration. Rectal administration offers ease of use but the variation in absorption and first-pass metabolism from patient to patient can make efficacy unpredictable. Furthermore, rectal dosing cannot be used in the setting of diarrhea, transmucosal lesions, neutropenia, or severe thrombocytopenia. Transdermal administration may be useful when the oral route is unavailable; however, this dosing method is limited by the amount of available skin surface and is not effective for control of fluctuating pain levels. Intramuscular administration should, in general, be avoided because of erratic absorption and pain associated with the procedure.

Patient-controlled analgesia (PCA) devices allow patients to adjust opioid delivery according to their level of pain. PCA may be used for initiation of parenteral opioid therapy, rapid opioid titration, or treatment of incident pain. The devices are programmed for dose size, lockout interval, and cumulative dose allowable over a given period; continuous infusion may be programmed to supplement PCA doses, enabling sleep and covering baseline pain. Safety features prevent the delivery of more medicine when the patient is excessively sedated. Compared with conventionally administered opioids, PCA provides equivalent or superior analgesia with less total opioid consumption,fewer side effects, and no greater likelihood of dependence. PCA may be used in the home, allowing severely ill patients to receive adequate pain relief outside of the hospital.

Intraspinal opioid administration is useful for patients requiring such large amounts of opioids that systemic side effects prevent the maintenance of adequate drug levels. Delivery of opi-oids to the epidural or intrathecal space exploits the large concentration of opioid receptors in the dorsal horn of the spinal cord, achieving analgesia at significantly smaller doses of opioid than would be required with systemic administration. Compared with the intravenous route, intrathecal and epidural morphine are 100 times and 10 times more potent, respectively. The smaller opioid doses required for intraspinal administration result in effective analgesia at a greatly reduced side-effect burden. Implantable intrathecal drug delivery systems consist of an implanted programmable pump that delivers small doses of morphine directly to the spinal fluid. Although intraspinal opioid therapy has obvious benefits, it is not a first-line treatment. It is indicated only for patients who have experienced some degree of pain relief in multiple trials of different systemically administered opioids but who have suffered intolerable side-effect burdens that effectively prohibited the continued use of these regimens.

Desired duration of drug action varies with clinical circumstances. Long-acting and sustained release formulations are useful for patients in continuous pain; these drugs reduce severity of end-of-dose pain and may let patients sleep through the night. Sustained-release formulations are frequently used to treat patients with cancer pain. Most opioids may be given on an around-the-clock or an as-needed basis, but around-the-clock administration may improve patient outcomes and adherence. Long-acting formulations also may improve patient adherence. Short-acting formulations are used to manage intermittent pain and breakthrough pain.

Dosing

Titration to optimal dosage generally involves gradual adjustment of a small initial dose, on the basis of both the pain relief achieved and the severity of side effects encountered. A patient may be given an immediate-release oral formulation of an agent with a short half-life for a limited time (e.g., 24 to 48 hours), during which medication consumption, efficacy of pain relief, and side effects encountered are recorded in a patient diary. Alternatively, patients in severe pain may need rapid titration of a potent opioid via continuous intravenous infusion. Once pain control has been achieved and the optimal dose determined, the opioid may (if desired) be prescribed in long-acting or sustained-release form.

The opioid dose required to control pain in a given patient is influenced significantly by the type and severity of pain, any preexisting opioid tolerance, psychological distress, age, and genetic factors. Changes in dose may be required if pain severity increases. In general, dose changes should be made in increments of one third to one half the prior dose and should be modified according to the patient’s use of breakthrough medications. This formula also applies to the reduction or cessation of opioid dose in patients whose source of pain is eliminated. Gradual reduction of the daily dose (i.e., reductions in increments of less than 25%) is necessary to prevent symptomatic withdrawal.

Patients receiving long-acting opioid therapy may experience episodes of acute pain that cannot be adequately controlled by the baseline analgesia provided by long-acting opioids. Short-acting, immediate-release opioids are used to cover this break through pain and are a critical component of long-term opioid therapy. There is no standard methodology for the dosing of breakthrough medications. Single rescue doses are commonly set at either 10% to 20% of the total daily dose or 25% to 30% of the single standing dose. As is the case with standing doses, breakthrough doses should be adjusted as appropriate for the individual patient. When possible, the same agent should be used for standing and breakthrough medications; this approach eases titration and eventual conversion (see below).

Weak opioids often are compounded with a nonopioid analgesic (commonly, acetaminophen). This combination may result in an opioid dose-sparing effect; however, it does not consistently reduce side effects. In addition, the potential for overdose of the nonopioid component limits escalation of the opioid dose. This may necessitate a switch to another opioid or combination if pain increases in severity.

Opioid Conversion

Although there is no theoretical upper limit to the dose of most opioids, practical ceilings for a given agent may be imposed by side effects, administration concerns (e.g., excessive in-jectate volume or skin surface area required for patches), or lack of apparent response to the drug. Such impediments to dose escalation may require switching of agent, route of administration, or both. When changing from one agent to another is necessary, clinicians often make use of published equianalgesic conversion charts. However, these standardized tables were constructed on the basis of limited data; therefore, they should serve as only a starting point for opioid conversion dosing.

Consideration of opioid conversion because of increasing pain should begin with a comprehensive assessment of the nature of the pain necessitating the switch. Pain caused by a worsening underlying medical condition may require a change in the treatment of that condition in addition to, or in place of, a change in analgesic. Pain attributable to inflammatory or neuropathic etiologies may be better treated with adjuvant analgesics than with a modification of opioid therapy. Pain purely attributable to opioid side effects may simply require treatment of the adverse effects (see below). Opioid conversion for refractory pain or intolerable side effect burden is justified if the pain is opioid-re-sponsive, the current analgesic has been titrated to maximal effect, and side effects are already optimally managed.

Little evidence supports a particular selection order of opioid analgesics. The choice of a new agent may be made on the basis of such factors as the patient’s prior experience with opioids of a given class or receptor profile. Once the new agent has been selected, equianalgesic conversion tables should be consulted to arrive at a starting point for dosing [see Tables 3 and 4]. If the patient had been receiving multiple opioids, conversion should be based on the total dose of all prior agents, expressed as morphine equivalents. The calculated dose should then be individualized according to the nature and severity of the patient’s pain. If opioid conversion was necessitated by intolerable side effects in the setting of adequate pain control, the calculated dose should be reduced by approximately 25% to 50%; this will allow for the lack of cross-tolerance among agents. Alternatively, if conversion was prompted by inadequate analgesia and significantly impaired quality of life, the new agent may be started at or near an equianalgesic dose. Additional short-acting opioids should be made available to the patient during titration of the new drug in order to achieve stable analgesia. Breakthrough medication is especially important during opioid conversion.

Continuous reassessment of the patient’s pain and total daily dosage (extended release plus immediate release) should occur for the first 2 weeks after opioid conversion, with titration of the extended-release and breakthrough doses as appropriate. Both inadequate pain control and excessive narcosis are threats in the immediate conversion period.

Patients whose pain cannot be controlled with opioids should be considered for invasive pain control modalities. In general, however, such modalities should not be explored until adequate trials of several opioids have been completed.

Opioid Side Effects

Sedation Most patients experience sedation with initiation of therapy or an increase in dosage, but this sedation commonly resolves within 3 to 7 days; chronic sedation occurs in a small minority of patients. Sedation is a special concern in the elderly and in patients taking other sedating medications. Sedation may also reflect the relief of pain itself, as patients recoup rest previously lost to discomfort. Nonessential medications with sedating effects should be eliminated in patients experiencing opioid-relat-ed sedation. Stimulants such as caffeine or methylphenidate should be considered for use in cancer patients with significant persistent sedation, although the use of psychoactive medication in the elderly should always be approached with caution.53 Stimulants are not recommended for patients experiencing sedation caused by opioid management of chronic pain.

Nausea Opioids may cause nausea and vomiting by both central and peripheral mechanisms. Centrally, opioids directly stimulate the chemoreceptor trigger zone in the medulla. Peripherally, opioids slow gastric motility. Additionally, many patients receiving opioid therapy will also have medical comorbidities or will be receiving treatments (e.g., chemotherapy) that contribute to nausea and vomiting. Use of a variety of antiemetics during the first 1 or 2 days of opioid administration may successfully control nausea and vomiting. Ondansetron, prochlorperazine, or hydroxyzine may alleviate centrally-induced nausea, whereas metoclopramide may reduce nausea from slowed gastric motili-ty. Scopolamine may alleviate motion-exacerbated nausea in ambulatory patients.54 Anticholinergic side effects of common antiemetics may be clinically significant, particularly in the elderly. As is the case with sedation, nausea and vomiting frequently resolve shortly after onset of treatment.

Constipation Constipation is a common and clinically significant side effect of all opioids. It is caused by decreased peristalsis and intestinal secretions and increased electrolyte and water re-sorption in the large intestine. Additional risk factors for constipation include advanced age, impaired mobility, concurrent medications with constipating side effects, and gastrointestinal comorbidities. Unlike sedation and nausea, constipation does not improve with time. This side effect is underdiagnosed and may lead to anorexia, vomiting, abdominal pain, obstruction, im-paction, and perforation.

Dietary changes to prevent constipation should be implemented with opioid administration. All patients on around-the-clock opioids should undergo regular assessment for constipation and be given a stool softener and a stimulant laxative. Additional agents may be used if constipation is severe or persists; prolonged absence of bowel movements should result in assessment for fecal impaction, with treatment if necessary. Peripheral opioid antagonists are currently being tested and may prove useful.

Respiratory depression Respiratory depression, caused by direct inhibition of brain stem respiratory centers when the dose is escalated too rapidly, is a rare side effect of opioid therapy. Respiratory depression is primarily of concern in opioid-naive patients receiving large opioid doses; it also may be seen in the setting of head injury or concurrent pulmonary disease. Sedation level and respiratory status should be monitored regularly during the first 24 hours of therapy in opioid-naive patients. If respiratory depression occurs, the opioid may be stopped until the depression resolves, after which therapy may be continued at 75% of the previous dose. Spirometry and supplemental oxygen may be useful in these patients. Severe respiratory depression may be treated with intravenous naloxone.54 Fear of respiratory depression should never preclude the effective delivery of pain relief.

Confusion Opioid-induced neurotoxicity is a relatively recently identified syndrome that occurs primarily in patients receiving high-dose or prolonged opioid therapy and in those with decreased renal function.55 Patients with previous cognitive impairment are at additional risk. Delirium, agitation, myoclonus, and hyperalgesia are features of this condition. Confusion is a side effect of particular concern in the elderly or in patients with concurrent CNS disease. Nonessential medications with CNS effects should not be prescribed for elderly patients requiring opi-oid therapy. Neuroleptics may be useful against confusion, mental clouding, or persistent delirium.

Other side effects Pruritus secondary to histamine release is an additional opioid side effect; it is generally managed with diphenhydramine or hydroxyzine. Myoclonus may be treated with clonazepam. Urinary retention, vertigo, sweating, and hypotension are less frequently reported side effects of opioid therapy.