Tolerance, Physical Dependence, and Psychological
Dependence
Tolerance Tolerance occurs when exposure to a drug changes the dose-response relationship, such that a higher dose of agent is required to maintain a given effect. There is no clinical limit to tolerance, and wide ranges of opioid requirements have been reported. Patients in the last 4 to 6 weeks of life require an average of 400 to 600 mg of morphine equivalents per 24 hours, and up to 10% of patients require more than 5,000 mg.56 As noted, opioids do not have a ceiling effect per se and may be titrated to very large doses as required for optimal pain relief. Progression of side effects with increasing dosage may be managed with opioid rotation, adjuvant analgesic drugs, and epidural local anesthetics. Tolerance rarely develops in patients with stable disease; increasing requirements in the setting of previously controlled chronic pain should prompt a comprehensive medical evaluation.
Physical dependence Physical dependence describes a state of adaptation, often including tolerance, in which a drug class-specific withdrawal syndrome could be produced by abrupt cessation of drug administration, rapid reduction in dose, decreasing blood level of drug, or administration of an antagonist or mixed agonist-antagonist. Physical dependence is virtually universal with prolonged opioid therapy; to avoid withdrawal syndrome, all patients receiving opioids for 1 week or longer should have the drug tapered off rather than abruptly discontinued.
Psychological dependence Psychological dependence, or addiction, is a primary, chronic, neurobiologic disease whose development and manifestations are influenced by genetic, psychosocial, and environmental factors. Addiction is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving. The psychologically dependent person has a consuming involvement with drug use, which typically results in a range of social, vocational, economic, and legal difficulties.
Fear of addiction on the part of both physicians and patients is a significant cause of underutilization of opioids in the treatment of pain, yet this fear is largely unfounded. Numerous studies have shown that the prevalence of psychological dependence in patients receiving opioids for the relief of pain is extremely low—0.03%, in one study.47
More common in this population is pseudoaddiction, a condition in which patients with poorly managed pain mimic many of the signs of psychological dependence. Pseudoaddiction is characterized by drug seeking, or an increased focus on obtaining medications, and possibly illicit drug use or deception. The defining distinction between addiction and pseudoaddiction is that pseudo-addiction behaviors resolve with effective pain management. As such, pseudoaddiction is best managed with effective pain relief and is likely to be exacerbated by the curtailing of opioid therapy.
Nonsteroidal anti-inflammatory drugs and acetaminophen
Indications
NSAIDs, acetaminophen, or both may be employed against a variety of types of acute and chronic pain. They are especially useful for certain types of somatic pain, including muscle and joint, bone, dental, postoperative, and inflammatory pain. These drugs may provide sufficient relief for mild or moderate pain. In the setting of severe pain, they may be added to an opioid regimen for their opioid-sparing effect. Combination opioid-nonopi-oid therapy may allow for enhanced pain relief with reduced side effect burden.
Mechanism
NSAIDs act primarily through inhibition of cyclooxygenase, thereby decreasing prostaglandin synthesis. Nonselective NSAIDs inhibit both COX-1 (a normal constituent of blood vessels, stomach, and kidney) and COX-2 (an enzyme induced in the setting of peripheral inflammation); COX-2 inhibitors selectively inhibit the COX-2 enzyme. All NSAIDs have analgesic, anti-inflammatory, and antipyretic effects. Acetaminophen works via a central mechanism; its actions are primarily analgesic and antipyretic.
Administration Route and Formulation
Most NSAIDs and acetaminophen are taken orally, although other routes of administration exist. Numerous formulations are available without prescription. In addition, combinations of NSAIDs or acetaminophen with opioids or members of other drug classes are commonly used.
Dosing
Dosing amount and frequency vary across preparations [see Table 5]. NSAIDs and acetaminophen exhibit a dosage ceiling, beyond which additional side effects accrue without additional therapeutic benefit.
Side Effects
Exact side effect profiles vary with individual drugs, but non-selective NSAIDs as a class exhibit certain characteristic side effects, including gastrointestinal disturbances, bleeding, hypersen-sitivity, and CNS effects. In addition, nonselective NSAIDs have nephrotoxic potential, especially in patients with renal dysfunction who require prostaglandins for maintaining renal vasodilata-tion. NSAID side effects are often dose dependent; use of these drugs at low doses for short periods may minimize their impact. Additionally, preventive strategies may be employed, such as coadministration of gastrointestinal tract-protective drugs (e.g., lansoprazole, esomeprazole, or misoprostol). Although the reputation of selective COX-2 inhibitors was tarnished by the discovery of life-threatening side effects with rofecoxib and valdecoxib and the subsequent withdrawal of these agents from the market, celecoxib remains a very helpful agent for some patients, particularly those with low or no risk of coronary artery or cerebrovascu-lar disease. Nonopioids have a ceiling effect for analgesia; increasing dosage above a certain level will increase side effect burden without yielding enhanced analgesia. Neither tolerance nor physical dependence is seen with NSAID use.
Table 5 Nonopioid Analgesics Commonly Used for Mild to Moderate Pain
|
Drug Name |
Starting Oral Dose (mg) |
Comments* |
|
Aspirin |
650 |
Often used in combination with opioid analgesics; reduces platelet function; avoid in pregnant patients and those with clotting disorders; avoid concomitant use with steroids |
|
Choline magnesium trisalicylate |
1,500 |
Does not affect platelet function |
|
Acetaminophen |
650 |
Does not affect inflammation or platelet function; use with caution in patients with hepatic dysfunction |
|
Ibuprofen |
200-400 |
Higher analgesic potential than aspirin |
|
Diflunisal |
500-1,000 |
Longer duration of action than ibuprofen |
|
Naproxen |
250-300 |
Longer duration of action than ibuprofen |
|
Ketorolac tromethamine |
10 |
Do not use for more than 5 days; I.M. formulation can be given in dose of 30 mg |
|
Tramadol |
50-200 |
Weak mu agonist and serotoninergic and catecholamine reuptake inhibitor |
|
Celecoxib |
100-200 |
Cyclooxygenase-2 inhibitor; contraindicated in sulfa-allergic patients |
*Except for acetaminophen, tramadol, and celecoxib, all these drugs are nonselective nonsteroidal anti-inflammatory agents and share the side effects of this class of agents [see text].
Acetaminophen provides pain relief comparable to most NSAIDs without the gastrointestinal disturbances and bleeding seen with NSAIDs. Acetaminophen must be used with caution, if at all, in patients with liver disease. In patients with normal livers, however, hepatic toxicity is rare with dosages beneath the ceiling of 3 to 4 g/day.
Corticosteroids
Indications
Corticosteroids are the most widely used general adjuvant analgesics.57 In the setting of cancer, they are especially useful for relief of acute pain associated with spinal cord compression, increased intracranial pressure, superior vena cava syndrome, metastatic bone pain, neuropathic pain secondary to infiltration or compression by tumor, and hepatic capsule distension. High-dose corticosteroids are often used for inpatients with advanced disease who are in acute pain crisis.58 Corticosteroids are commonly used for pain related to musculoskeletal conditions.
Mechanism
Steroids act through an anti-inflammatory mechanism. They also produce glucocorticoid and mineralocorticoid effects.
Administration Route and Dosing
Corticosteroids are commonly given in oral or injectable form. Dosing varies with agent and indication.
Side Effects
Steroids are generally well tolerated for short-term treatment; however, toxicities often arise with prolonged high-dose therapy. Common toxicities include adrenocortical insufficiency, hypertension, immune suppression, the masking of signs of infection, glaucoma, electrolyte imbalances, gastrointestinal ulcera-tion and bleeding, osteoporosis and pathologic fracture, and psychiatric disturbance or psychosis. Care must also be taken to prevent withdrawal syndrome upon discontinuance.
Antiepileptic drugs
Indications
Antiepileptic drugs (AEDs) such as gabapentin, carbamaz-epine, and topiramate may be useful as adjuvant drugs in the treatment of a variety of forms of neuropathic pain, including peripheral diabetic neuropathy, postherpetic neuralgia, reflex sympathetic dystrophy, trigeminal and glossopharyngeal neuralgia, HIV neuropathy, and spinal cord injury-related dysesthe-sias. These agents are also useful for postlaminectomy, phantom limb, and cancer pain.
Considerable clinical data suggest that gabapentin should be a first-line treatment for neuropathic pain, because of its greater clinical efficacy and a more favorable side effect profile than seen with older AEDs and other agents such as tricyclic antidepres-sants (TCAs).59,60 Gabapentin does not interact with other drugs. Carbamazepine should be considered as only a second- or third-line agent for most neuropathic pain conditions. However, car-bamazepine remains the first-line treatment for trigeminal neuralgia [see 11:II Diseases of the Peripheral Nervous System]. Topira-mate is increasingly used off-label as an adjuvant analgesic agent for neuropathic pain.
Mechanism
The exact mechanism of the analgesic effect of AEDs is unknown. These agents reduce membrane excitability, thereby possibly suppressing discharges from pathologically altered neurons, likely primarily by the inhibition of sodium channel transmission.
Administration Route and Dosing
AEDs are administered orally. Current guidelines recommend starting gabapentin at a dosage of 100 mg every 8 hours; however, optimal control of neuropathic pain often requires titration to 3,600 mg a day in divided doses. Topiramate must be titrated slowly (i.e., no faster than 25 mg a week) to decrease the incidence of side effects. Although daily doses of up to 400 mg are used for epilepsy, 100 to 200 mg is a more typical dose for pain. Dosing of other AEDs varies with agent and indication.
Side Effects
Gabapentin is generally well tolerated; some patients experience mild sedation and gastrointestinal effects. However, elderly patients often have poor tolerance of gabapentin because of cognitive effects, particularly at higher dose levels. Topiramate can cause cognitive slowing and paresthesias, especially with overly rapid titration.
The most common side effects seen with other AEDs include sedation, nausea and vomiting, and dizziness. Carbamazepine may cause thrombocytopenia or liver damage. Phenytoin may induce dose-related CNS effects, as well as hepatotoxicity, hypersensitivi-ty reactions, and lymphadenopathy at high serum concentrations.
Antidepressants
Tricyclic Antidepressants
Indications Amitriptyline, nortriptyline, imipramine, and other TCAs are frequently used as adjuvant analgesics in the treatment of a variety of types of neuropathic pain (e.g., painful diabetic neuropathy, postherpetic neuralgia, chronic facial pain, central pain) and chronic pain (e.g., cancer pain, chronic low back pain, osteoarthritis). TCAs have efficacy equivalent to AEDs in the treatment of certain types of neuropathic pain.61 Efficacy is comparable among most TCAs.
Mechanism The analgesic effect of antidepressants may derive from the inhibition of norepinephrine and serotonin reup-take in the CNS, thereby increasing the activity of endogenous pain suppression pathways.
Administration route and dosing TCAs are taken in oral form. Although the effect of these agents may be seen at low doses, achieving optimum analgesic efficacy may require higher dose titration. Amitriptyline, desipramine, doxepin, and nor-triptyline are typically started at a dose of 10 to 25 mg and may be titrated to a maximum daily dose of 150 mg, if tolerated.
Side effects Common side effects of TCAs as a class include anticholinergic effects such as sedation, hypotension, constipation, and urinary retention; the elderly are most susceptible to these effects. Amitriptyline has the strongest anticholinergic profile and for that reason is given at bedtime; nortriptyline, which has a less prominent anticholinergic profile, is generally a better choice for older patients. At doses above those typically prescribed for pain, lethal cardiac arrhythmias may occur; thus, these medications are contraindicated in patients with conduction abnormalities.
Selective Serotonin Reuptake Inhibitors
Overall, selective serotonin reuptake inhibitors (SSRIs) have been disappointing as primary analgesic agents compared with TCAs and AEDs, despite their favorable side effect profiles. Both paroxetine and venlafaxine (which blocks reuptake of norepineph-rine as well as serotonin) have been shown in randomized controlled trials to be useful in managing neuropathic pain, but both agents are generally considered to be second-line choices; they are used when refractoriness or poor tolerability has been demonstrated with other agents such as TCAs, AEDs, and opioids.
Topical analgesic agents
There has been a growing interest in the role of topical therapy in the management of neuropathic pain. The enthusiasm has been partly driven by the discovery of the role of peripheral no-ciceptor modulation in dampening pain transmission and partly by the perpetual difficulty in certain populations with tolerabili-ty of systemic medications.
Transdermal Lidocaine
Approved by the Food and Drug Administration for the treatment of postherpetic neuralgia in 1999, the 5% lidocaine patch is now a first-line agent in managing postherpetic neuralgia. Patients are instructed to wear the patch for 12 consecutive hours over the area of pain and to then discard it; they are further instructed to wait to apply a new patch until another 12 hours have passed. One to three patches can be used at any one time, depending on the surface area of the pain site. There have been reports that transdermal lidocaine is effective in other painful conditions, such as low back pain, but few published data support the use of this patch in conditions other than postherpetic neuralgia.
EMLA
EMLA cream (lidocaine 2.5% and prilocaine 2.5%) has been shown to be very effective in children undergoing painful procedures, such as needle insertions and blood draws. Its role in managing neuropathic pain has yet to be demonstrated.
New approaches
Patients with pain have benefited enormously in the past 10 to 15 years from the attention paid to the mechanism of pain, which has moved the field of pain research from empiricism to scientific validity. Several drugs have sprung from such scientific discoveries; some are now in development and some have been approved for use.
Ziconotide
Approved by the FDA in 2004, ziconotide is a synthetic version of a South Pacific marine snail toxin that blocks calcium transmission. It is 1,000 times more potent than morphine and thus may only be delivered intrathecally by an implantable pump.
Duloxetine
Duloxetine, a norepinephrine and serotonin reuptake inhibitor, was approved by the FDA in 2004. Its main indication is for burning peripheral neuropathy, although there is hope that it may be helpful as an antidepressant as well, in view of its mechanism of action.
Capsaicin
Capsaicin contains the ingredient in chili peppers that causes a burning sensation. Although a weak formulation of capsaicin has been available over the counter for many years, trials are now under way of a far more potent version, which may decrease pain more successfully by dampening pain transmission at the skin receptor level.
Pregabalin
The success of gabapentin as a first-line agent for neuropathic pain has resulted in the development of the related compound pregabalin, which is expected to be introduced in the United States in the second half of 2005. Although the mechanism of action of pregabalin is similar to that of gabapentin, there is hope that this newer agent may be useful as an alternative when patients do not respond adequately to other agents.
