Pharmacologic Management of Acute and Chronic Pain.

Focus on Drug Interactions and Patient-Specific Pharmacotherapeutic Selection

PAIN is among the most common reasons patients seek medical care. Acute and chronic pain is debilitating. Recovery is slow, interference with daily activities occurs, and pain manifests as a decremental change in the patient's quality of life. This is compounded by societal costs. [1-5]

Acute pain is often associated with an identifiable injury or trauma as a known antecedent, responds to therapeutic options, and resolves in less than i to 3 months, chronic pain is more of a treatment challenge because the pathogenesis may be unclear, with less opportunity to predict the course of recovery. For patients already under great psychologic and financial stress, such an ambiguous prognosis is devastating. The goal of the clinician is to provide an opportunity for patients to regain some sense of control over their lives by providing the most effective pain treatment regimen possible. [1-5]

Pain usually defined as chronic lasts longer than i to 3 months or exceeds the typical recovery time for an initial injury, chronic pain may be continuous or episodic or a combination of both. Overall, chronic pain is commonly accompanied by emotional stress, increased irritability, depression, social withdrawal, financial distress, loss of libido, disturbed sleep patterns, diminished appetite, and/or weight loss, chronic pain can have a wide-ranging impact; its management must therefore focus on multiple aspects of a patient's life. A multidisciplinary, comprehensive treatment plan is optimal, including (1) individual psychosocial counseling in conjunction with patient/family education; (2) noninvasive or minimally invasive procedures, such as massage therapy, physical therapy, transdermal or transcutaneous electrical nerve stimulation (TENS), or acupuncture; (3) up-to-date pharmacologic and/or anesthetic therapies; and (4) if necessary, surgical intervention and physical medicine with rehabilitation focused to enhance the patient's functional status. Health care practitioners must consider uniting these various options in tailoring a patient-specific treatment plan, addressing both physiologic and psychologic symptoms. [1-8]

A pharmacotherapeutic plan begins with a thorough pain and pain medication history to identify the nature of the patient's pain (eg, acute versus chronic, acute and chronic, nociceptive versus neuropathic). The patient interview should focus on patient-reported pain descriptors (eg, exacerbation/modulation of pain; pain quality and intensity; pain sites as local, disseminated, or regional; characteristics and temporal relationships of pain), current pharmacotherapies (prescription, over-the-counter, phytopharmaceutical, and/or social/recreational agents), and past treatments (including successes and/or failures, adverse effects, and allergic reactions). A complete blood chemistry profile should be considered to determine if dosage changes are warranted. Health care practitioners should familiarize themselves with the pharmacodynamics, pharmacokinetics, and potential drugdrug or drug-food interactions and contraindications of any pharmacotherapy used by the patient. [1-3,7,9]

Decisions about a polypharmaceutical or other complex regimen may be made jointly. Depending on the nature of the specific pain in a given patient, combinations of antidepressants, anxiolytics, anticonvulsants, sedative/hypnotics, centrally acting agents, opiates/opioids, muscle relaxants, nonsteroidal anti-inflammatory drugs (NSAIDs), or other analgesics may be considered. Health care practitioners should also consider any factors that affect the likelihood of compliance (eg, patient age, frequency and/or complexity of the regimen, route of administration, tolerance of the regimen). [1-3,9]

Pharmacologic Agents

NONOPIOID ANALGESICS

An extensive review of these agents has been published elsewhere. Aspirin (acetylsalicylic acid [ASA]) is used to reduce inflammation, pain, and fever. It inhibits prostaglandin synthesis and acts on the hypothalamus to reduce fever, to prevent the formation of the platelet aggregation substance thromboxane, and to inhibit vitamin K--dependent and independent clotting factors. Renal elimination of ASA is primarily as free salicylic acids and conjugated metabolites. Aspirin use should be avoided in end-stage renal disease. The dose should be modified when aspirin is used for long-term therapy in the presence of hepatic compromise. Side effects of aspirin include gastrointestinal (GI) irritation, nausea, vomiting, tinnitus, metabolic acidosis, acute respiratory distress syndrome, and occult GI blood loss. Both aspirin and salicylic acid enter the central nervous system (CNS), and effects such as dizziness, vertigo, fatigue, insomnia, lethargy, confusion, depression, and headache may occur. [1-3,8,10,11]

Caution should also be taken in treating patients with platelet or bleeding disorders or renal dysfunction. All patients receiving ASA for transient ischemic attacks or myocardial infarction who are prescribed a cyclooxygenase-2 (COX-2) agent must continue taking the ASA (80 ma to 325 mg). Patients with a history of nasal polyps, asthma, or rhinitis may have aspirin intolerance, leading to severe exacerbation of allergic symptoms, including potentially fatal bronchospasms.

Acetaminophen (APAP) is an analgesic and antipyretic agent that lacks anti-inflammatory properties. The APAP central mechanism may be mediated through central COX-2 mechanism. Metabolism occurs in the liver, primarily by cytochrome P450 (CYP-450) 1A2, 3A4, and 2E1. A slight increase in the dosing interval may be needed when renal dysfunction is present. Prolonged use of APAP in patients with severe liver disease is not recommended. Hepatotoxicity may occur with daily long-term doses of more than 3,000 mg/day and short-term doses of 7 to 8 a and is exacerbated in patients with a history of alcohol abuse. No more than 3 to 4 g of APAP daily is currently recommended. [1-3]

Nonsteroidal anti-inflammatory drugs are antipyretic, anti-inflammatory, and analgesic agents that decrease prostaglandin production through their variable inhibition of cyclooxygenase-1 (COX-1) and COX-2. All NSAIDs carry the risk of GI, hepatic, hematologic, and renal adverse effects, which should be considered when contemplating their use long-term for pain. Drug monitoring should include complete blood count, creatinine clearance, urinalysis, potassium level, liver function tests, occult fecal blood testing, and blood and urine testing for hematuria and proteinuria. Gastrointestinal ulceration, bleeding, and perforation occur, often without warning symptoms. [1-3,11,12]

Other adverse effects associated with NSAID use include reduced renal blood flow and glomerular filtration, interstitial nephritis, acute tubular necrosis, papillary necrosis, nephrotic syndrome, sodium and water retention (edema), acute renal failure, hyperkalemia, and hypertension; NSAIDs also decrease the efficacy of diuretics, [beta]-blockers, and angiotensin-converting enzyme (ACE) inhibitors. Elderly patients, patients with diabetes mellitus, or those with mild to moderate renal insufficiency may be predisposed to hyperkalemia, as may patients receiving concomitant therapy with other hyperkalemia-inducing agents (ACE-inhibitors, potassium-sparing diuretics, salt substitutes). Local as well as systemic injury is caused by prostaglandin synthesis inhibition of gastric mucosa defense and platelet function, respectively. Inhibition of platelet aggregation can lead to enhanced bleeding. [1-3,11,12]

Two isoenzymes of oral cyclooxygenase--COX-1 and COX-2--have been identified. Only two COX-2 specific agents are currently available in the United States. A comparison of these two agents is seen in the Table. The distribution, regulation, and function of cyclooxygenase, along with a complete review of COX-1 and COX-2 agents, has been fully described elsewhere." [11,12]

Acute sodium retention is COX-2 inhibitor--mediated and clinically resolves with continuation of therapy. Glomerular filtration rate (GFR) is influenced due to inhibition of COX-1; COX-2 specific agents spare the GFR, which decrementally deteriorates in the elderly. Both hypertension and edema are of minor clinical occurrence with COX-2 specific agents. As with all NSAIDs, COX-2 agents should be used with caution in patients with fluid retention, hypertension, or heart failure. Rofecoxib has been found to be opioid-sparing in postoperative treatment of pain. Rofecoxib has prominent pharmacologic, pharmacokinetic, pharmacodynamic, and pharmacotherapeutic advantages over the available COX-2 specific agents. [3,11,112]

CENTRALLY ACTING ANALGESIC

Tramadol is an atypical analgesic with a binary mechanism of action. The mechanism of action combines centrally acting opioid ([micro]) activity with a secondary spinal mechanism of monoamine reuptake inhibition. With its weak affinity for [micro]-opioid receptors, in conjunction with serotonin and norepinephrine reuptake blockade, tramadol interferes with pathways that mediate pain. Spinally and supraspinally, tramadol is associated with a lower degree of respiratory depression than opioids. It has a low potential for tachyphylaxis and abuse and is used for the long-term management of moderate to moderately severe pain and for acute pain. The concomitant use of tramadol and NSAIDs (eg, rofecoxib) may offer the therapeutic benefits of both central and peripheral analgesia, though the requisite studies have not yet been concluded. Tramadol represents an option for patients who are at risk for the side effects of NSAIDs but are reluctant to take opioid analgesics. Only 20% is bound to plasma proteins. The activ e metabolite Ml and the parent exhibit linear pharmacokinetics, utilize the CYP45O 3A4 and 2D6 hepatic enzyme substrate, respectively. Dialysis removes less than 10% of a given dose.

Tramadol has been additionally studied in elderly populations and for a variety of conditions. It has been well tolerated overall and has proven to be effective in fibromyalgia, acute or chronic pain, osteoarthritis, back pain, and neuropathic pain. In the near future, tramadol will be available in combination with APAP (37.5 mg tramadol and 325 mg APAP), in a sustained-action dosage form, and in an oral liquid form. [1-3,6,13-18]

OPIATES AND OPIOIDS

Probably the best-known class of medications used to treat pain is that of the opiates and opioids. When opiates are used for management of chronic pain, both chemical and psychologic dependence may ensue with chronic administration. Both practitioners and patients can have "opiophobia" (the patient's fear of opiate use, the physician's concern of "opiate addiction," and the pharmacist's cautions about dispensing the prescription), which leads to unnecessary underutilization of opiates in pain management.

Opiates/opioids each uniquely produce a wide spectrum of pharmacologic effects, including analgesia, dysphoria, euphoria, somnolence, respiratory depression, diminished GI motility, altered circulatory dynamics, urinary retention, histamine release, and physical dependence. [1-5,7,11,19-23]

The analgesic effects appear to be a function of several factors, including affinity for specific receptor binding sites, intrinsic activity at respective receptors, and the pharmacokinetics and pharmacodynamics of the specific agents. The binding of [micro] receptors ([[micro].sub.1] and [[micro].sub.2]) produces euphoria and is associated with morphine-like analgesia, respiratory depression, miosis, and inhibited GI motility. The [[micro].sub.2] receptor has been associated with effects on GI motility, euphoria, respiratory depression, bradycardia, and psychologic aspects of chemical dependence.

Codeine is metabolized to morphine, and hydrocodone is metabolized to hydromorphone. This hepatic metabolism occurs through the CYP-450 2D6 pathway. (A brief comment on each frequently prescribed opiate/opioid follows.) Hydrocodone, a phenanthrene derivative, is a dehydrogenated ketone codeine derivative. Fixed hydrocodone analgesic combinations include APAP and ibuprofen. Most opioids have side effects, including sedation, nausea, vomiting, pruritus, and urinary retention. Constipation is an adverse effect to which tolerance does not develop, so a laxative and/or stool softener may be added to opiate/opioid therapy.

Morphine dosage should be administered according to the patient's characteristics. Elderly patients are more sensitive to morphine. Dose adjustments are not necessary in mild hepatic disease, but excessive sedation occurs in cirrhotic patients. This is a function of the accumulation of the active analgesic metabolite, morphine-6-glucuronide (M-6-G), which is renally eliminated. Oxycodone is an analgesic metabolized by the CYP-450 2D6 isoenzyrne and is excreted renally. Oxymorphone is a minor active metabolite of oxycodone created through hepatic CYP-450 metabolism.

Morphine acts as a pure agonist, binding with and activating opioid receptors at sites in the periaqueductal and periventricular grey matter, ventromedulla, and spinal cord to produce analgesia. The principal therapeutic actions of morphine on the CNS are analgesia, sedation, and alterations of mood. The pharmacologic activity is primarily due to the parent compound morphine. One metabolite, M-6-G, has been shown to have analgesic activity, but it crosses the blood-brain barrier poorly and may accumulate during renal dysfunction or excessive administration. Elimination of morphine is primarily via hepatic metabolism by phase II process to glucuronide metabolites (55% to 56%), which are then renally excreted. The terminal half-life of morphine is 2 to 4 hours and up to 15 hours with linear pharmacokinetics over the dosage range of 30 to 100 mg. After the administration of oral morphine, approximately 50% of the morphine is not used, because of presystemic (CYP-50 metabolism, first pass) elimination; only abou t 20% to 40% of the administered dose reaches the systemic circulation.

Morphine is 30% to 35% reversibly bound to plasma proteins. The major pathway of the detoxification of morphine is conjugation. Virtually all morphine is converted to glucuronide metabolites, including morphine-3-glucuronide (M-3-G) (about 50%) and M-6-G (about 5% to 15%). While M-3-G has no significant, analgesic activity, M-6-G has been shown to have opioid agonist and analgesic activity in humans.

Meperidine is a synthetic opioid. Normeperidine is an active nonopioid metabolite that is clinically important in that it is not naloxone-reversible. The half-life of normeperidine is 15 to 30 hours, depending on the patient's renal function. After repeated dosing, normeperidine accumulates, and the concentration exceeds that of meperidine in the plasma. Resultant effects of normeperidine include respiratory arrest and excitatory neurotoxicity (hyperreflexia, myoclonus, grand mal seizures, and agitation). These effects have been reported after less than 24 hours of dosing in patients at all ages and in those with normal renal function as well as in those with impaired renal function. Anticholinergic effects of meperidine are serious enough that the patient may have urinary retention and need catheterization; other effects include ventricular response to atrial flutter and supra-ventricular tachycardia.

Meperidine also blocks the neuronal reuptake of serotonin with a serotonin syndrome produced by monoamine oxidase inhibitor (MAOI) drug interactions. Deaths related to meperidine-MAOI interactions have been reported. Serotonin syndrome has also been reported with concomitant use of meperidine and fluoxetine. Meperidine use may aggravate preexisting seizure disorders. Use of meperidine in chronic pain and acute pain is falling into disuse. [*]

Propoxyphene is a synthetic opiate analgesic with chemical similarity to methadone. It is metabolized in the liver to norpropoxyphene, which is eliminated in urine. Norpropoxyphene is not an opioid but has proarrhythmic lidocaine-like effects and cardiac anesthetic effects similar to those of amitriptyline. Because of its long half-life, norpropoxyphene accumulates if the parent drug is given repeatedly. Norpropoxyphene accumulation is associated with arrhythmias and pulmonary edema, and it is poorly dialyzed. There have also been reports of apnea, cardiac arrest, and death. Naloxone does not reverse the effects of norpropoxyphene. Long-term use of this agent is highly discouraged, and use in elderly patients is not recommended. The US General Accounting Office has listed propoxyphene among drugs "inappropriate for the elderly" and has emphasized that alternative analgesics are both more effective and safer. Propoxyphene use is generally discouraged. [1-4,7,8,10,11,19,25]

Fentanyl is a highly lipophilic opioid analgesic with agonist activity at the [micro]-opioid receptor in the brain, spinal cord, and smooth muscle. The transdermal patch is applied to the skin on alternating sites and is replaced every 3 days. One week should be allowed before altering the dose, and equilibration is not reached until 6 days after a dosage change. The transdermal delivery system offers continuous fentanyl administration. Increased fat stores, muscle wasting, or altered clearance should be a prescribing caution, and initial dosage should not be greater than 25 [micro]g/hr. A transmucosal (oral cavity) dosage form of fentanyl is also available.

Pentazocine, nalbuphine, and butorphanol are the mixed opioid agonist-antagonists. Nalbuphine and pentazocine must be used with caution in patients receiving opioids, to avoid precipitating withdrawal and increasing pain. Pentazocine is an agonist at both K and [sigma] receptors. Dysphoria, nightmares, depersonalization, and visual hallucinations are other adverse effects caused by pentazocine. Pentazocine use is discouraged. [1-3,7,11]

Butorphanol is an antagonist-agonist at the [micro] receptor. Therapeutic effects also may occur via agonist effects on the K receptor. Opiate abstinence may occur with coadministration of propoxyphene and methadone. Negative side effects can be minimized with administration in small doses, and a nasal deliver form is available. Nalbuphine has both agonist and antagonist properties. The most common adverse reaction is sedation. Buprenorphine is a partial agonist at the [micro] receptors and an antagonist at the K receptors. It may also have some antagonist activity at the [sigma] receptor but lacks dysphoric effects. Buprenorphine is anticipated to be available for oral administration. Buprenorphine has been used for analgesia without producing hemodynamic instability in the management of pain resulting from myocardial infarction. It has a lower incidence of nausea and vomiting than other opioids. Opiate abstinence has not been a clinical event with any coadministered opiates in our clinical practice. [+]

ANTIDEPRESSANTS

Selective serotonin reuptake inhibitors (SSRIs) have a limited side-effect profile. Adverse effects most commonly reported include headache, insomnia, anxiety, dizziness, tremors, drowsiness, nausea, vomiting, diarrhea, dyspepsia, xerostomia, sexual dysfunction, anorexia, and diaphoresis. Serotonin syndrome can occur when using SSRIs in combination with other medications, ie, MAOIs, dihydroergotamine, tryptophan, dextromethorphan, lithium, nefazodone, or "tryptans" that block the reuptake of serotonin. Selective serotonin reuptake inhibitors inhibit the CYP-450 enzyme system and cause delayed clearance of certain medications, especially those medications that use CYP-450 1A2, 2D6, and 3A4 enzymes as a substrate for their metabolism. All SSRIs can increase serum levels and decrease clearance of other substrate agents by way of these hepatic enzyme systems. The SSRIs are less effective than other antidepressants for the management of pain. A complete list of drug interactions involving the CYP-450 system and su bstrate drugs that may be used in the management of pain is provided in the Appendix. [1-3,5,7-10,25,27,29]

Among the tricyclic antidepressants (TCAs) is amitriptyline, which is hepatically converted to an active metabolite, nortriptyline. Imipramine is transformed by the liver to desipramine. Trazodone (not a TCA) is hepatically converted to meta-chlorophenyl piperazine (mCPP), a serotonin agonist, and is generally given at bedtime due to its sedative properties.

Generally, the adverse effects of TCAs result mostly from cholinergic/muscarinic receptor blockade, [[alpha].sub.2]-adrenergic blockade, histaminergic ([H.sub.1], [H.sub.2]) blockade, and dopaminergic blockade. Receptor blockade of cholinergic! muscarinic receptors can produce blurry vision, xerostomia, sinus tachycardia, constipation, urinary retention, and memory dysfunction. Blockage of [H.sub.1] and [H.sub.2] receptors produces sedation, dizziness, weight gain, and hypotension and potentiates CNS depressant agents. [[alpha].sub.1]-Adrenergic blockade is often associated with postural hypotension and dizziness. Dopamine-receptor blockade has been associated with extrapyramidal syndrome, dystonia, akathisia, rigidity, tremor, akinesia, neuroleptic malignant syndrome, tardive dyskinesia, and endocrine changes. Tachycardia and prolonged PR and QRS intervals with membrane stabilization occur. Orthostatic hypotension and, in patients who have impaired left ventricular function, congestive heart failure may occ ur. Bupropion (not a TCA) blocks reuptake of both norepinephrine and dopamine and also has relatively few cardiac side effects, minimal (if any) effects on cardiac conduction, and no production of orthostatic hypotension. [1-4,7,28-30]

Other receptor-specific antidepressants, such as venlafaxine, nefazodone, and mirtazapine, do not currently fit into any broad antidepressant classification. Venlafaxine (serotonin and norepinephrine reuptake inhibitor), has a complex mechanism of action. It blocks the reuptake of serotonin at low doses, blocks the reuptake of norepinephrine at medium doses, and blocks the reuptake of dopamine at higher doses. Venlafaxine is in effect three drugs in one because of such dose-related, receptor-mediated events. Venlafaxine provides the therapeutic benefits of tertiary and secondary amine antidepressants without the TCA side-effect profile. Venlafaxine also is beneficial in chronic pain, since it lacks clinically relevant CYP-450 interactions and is available in an extended release dosage form. [1-3,30,31]

Nefazodone is another antidepressant that acts dually on serotonin. Reuptake inhibition for 5-hydroxytryptamine (5-HT) and norepinephrine occurs, coupled with [5-HT.sub.2] receptor blockade. Some [[alpha].sub.1]-adrenergic inhibition produces orthostatic hypotension. This agent produces two active metabolites: the OH-nefazodone metabolite, which has activity similar to that of nefazodone, and the mCPP metabolite, which is the same metabolite found with trazodone. The mechanism of action of mCPP is that of a 5-HT agonist coupled with mild [5-HT.sub.2] and [5-HT.sub.3] antagonism. This agent shows zero-order kinetics. There is also relevant CYP-450 3A4 inhibition. [1-3,7]

Mirtazapine is an atypical antidepressant described as a noradrenergic serotonin-specific antagonist. This agent produces therapeutic antagonism at both [[alpha].sub.2] autoreceptors and heteroreceptors, thus facilitating enhanced noradrenergic and serotonin discharge. Mirtazapine's therapeutic benefits include a lack of sexual dysfunction, a decrease in migraine headache, and a decrease in anxiety, agitation, depression and insomnia. Further antagonism occurs at [5-HT.sub.2] receptors (decreasing anxiety and agitation) and at [5-HT.sub.3] receptors (decreasing nausea and GI distress). [H.sub.1]-receptor antagonism at low doses ([less than or equal to]30 mg) produces drowsiness, facilitating sleep and improving appetite. No clinically significant interactions are revealed in the CYP-450 system. A unique dissolve-in-mouth dosage form is available. Mirtazapine is a useful adjuvant agent in the management of chronic pain. [10-29-34]

ANXIOLYTIC AGENTS

The principal modulatory site of the [gamma] aminobutyric acid (GABA) receptor complex is found on its [alpha] subunit and is referred to as the benzodiazepine or [omega] receptor. Three subtype [omega] receptors have been identified, and it is thought that the [[omega].sub.1] receptor is associated with sedation and that [[omega].sub.2] is associated with anticonvulsant, anxiolytic, and myorelaxant effects. The clinical effects of the [[omega].sub.3] receptor have not yet been thoroughly investigated.

The [[omega.sub.2] receptors are associated with memory dysfunction, such as forgetfulness and/or amnesia, because of anterograde amnesic effects.

Clonazepam offers a therapeutic option among other benzodiazepines. Lorazepam, temazepam, and oxazepam may be especially useful to patients with liver impairment, because these drugs do not have any active metabolites and are metabolites and are metabolized by phase II processes. [**]

ANTICONVULSANTS

Anticonvulsants, or antiepileptic drugs (AEDs), have produced therapeutic benefits in a variety of painful neuropathic syndromes. Such agents include carbamazepine, phenytoin, vaiproic acid, tiagabine, gabapentin, oxcarbazepine, vigabatrin, zonisamide, lamotrigme, and topiramate and have been described elsewhere. [1-3]

Topiramate has several mechanisms of action (1) diminishing action potential by sodium channel blockade, (2) increasing GABA frequency activation at GABA receptor sites, (3) selectively antagonizing kainate activation at kainate/[alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropinate (AMPA) receptor sites, (4) providing glutamate antagonism, (5) calcium channel blockade, and (6) producing an acidosis that results in diminished N-methyl-D-aspartate (NMDA) mediated excitation and increased [GABA.sub.A] mediated inhibition. Additionally, some carbonic anhydrase inhibition occurs. Absorption is rapid with bioavailability of about 80%. The AMPA and kainate receptors have a role in mediating neuropathic pain. Pharmacokinetics are linear, with dose-proportional increases in plasma concentration, and the steady state is achieved in about 4 days. Plasma protein binding is only 13% to 17%. Metabolism is minimal, with 70% of a dose recovered unchanged in the urine; elimination half-life is 18 to 23 hours. The drug is cle ared by hemodialysis. Clearance is diminished in those patients with moderate renal impairment and/or hepatic impairment.

Side effects of topiramate include paresthesia and anorexia, to name a few. A [less than or equal to]% incidence of renal calculi requires adequate hydration. Central nervous system-related side effects are dose-related and are generally not observed at doses of less than 250 mg/day. Cognitive motor slowing and speech or work difficulty are seen only in a minimal percentage of patients when high doses are initiated, with rapid incremental dose changes, or with coprescription of other AEDs. In our clinical practice with a large number of patients, CNS event occurrence was not a clinically relevant finding. Clinical applications may be available for bipolar disorder, neuromodulation, neurostabilization and disease modification, obesity treatment, epilepsy, bulimia, neuropathic pain syndromes, essential tremor, and migraine headache.

SKELETAL MUSCLE RELAXANTS

Baclofen acts as a [GABA.sub.B] agonist in hyperpolarized membranes. Carisoprodol is metabolized in the liver by CYP-450 2C19 to an active metabolite, meprobamate. It should be avoided in patients with renal or hepatic disease. With prolonged use, this drug is associated with dependence. Use of carisoprodol is discouraged.

Cyclobenzaprine, a frequently used muscle relaxant, is structurally similar to TCAs. Side effects include drowsiness, dizziness, confusion, ataxia, xerostomia, and anticholinergic effects. Contraindications are similar to those of TCAs. Long-term use of cyclobenzaprine should be avoided, and the manufacturer recommends that administration not exceed a 3-week period. [1-3]

TOPICAL AGENTS

Capsaicin is a topical analgesic that may inhibit the synthesis, transport, and release of substance P, a peripheral neurotransmitter of pain. Capsaicin is used to treat pain associated with neuralgia, neuropathy, and arthritis. Lidocaine (5%) topical patches are available for the relief of allodynia (painful hypersensitivity) and chronic painful postherpetic neuralgia; the patches are to be applied for 12 hours daily only.

SLEEP-PROMOTING AGENTS

Treating disorders of initiating and maintaining sleep due to pain requires pharmacologic intervention when sleep hygiene methods have proved less than satisfactory. Selection of a pharmacologic agent necessitates pharmacodynamic and pharmacokinetic decisions that address a patient's specific needs. Zaleplon, a nonbenzodiazepine hypnotic, effects the [[omega].sub.1] receptor. Absorption is rapid, bioavailability is about 30%, and metabolism is primarily by aldehyde oxidase and by minor CYP-450 3A4 substrate-forming inactive metabolites. The mean half-life is about 1 hour. Therefore, the rapid onset, absence of active metabolites, absence of CYP-450 drug interactions of clinical consequence, rapid clearance from the body, and absence of major memory impairments make this agent highly suitable for use in patients with insomnia due to pain. [1-3]

MISCELLANEOUS AGENTS

Several other medications can be used to relieve pain. Clonidine and tizanidine are both imidazole [[alpha].sub.2]-agonists and are believed to inhibit pain transmission by modulating norepinephrine and 5-HT release in the dorsal horn on the lamina of the spinal cord. Potentiation of [micro]-opioid receptors and a decrease in the wide range of neuron excitability are additional mechanisms of [[alpha].sub.2] agonists, which also modulate specific calcium channels. Botulinum toxin type A has been used investigationally for some painful syndromes.

CONCLUSION

By following this pharmacologic review, the clinician is able to evaluate pharmacotherapies for a specific patient's needs, basing the selection on personal clinical experiences, patient-specific concerns, sides effects, adverse effects, drug interaction, pharmacodynamics, pharmacokinetics, and pharmacotherapeutics.

From the Departments of Anesthesiology, Family Medicine, Pharmacology, and Psychiatry, Rush Medical College and The Rush Pain Center at Rush Presbyterian St. Luke's Medical Center, Chicago, Ill; and The Pain Center of Rush North Shore, Skokie, Ill.

Reprint requests to Robert L. Barkin, MBA, PharmD, Rush Pain Center, 1725 w Harrison, Professional Bldg 3, Suite 550, Chicago, IL 60612.

(*.) Reference [1-3,5,7,8,10,11,19-22,24].

(+.) References [1-4,7,10,11,18-20,22,25,26].

(**.) References [1-3,9,19,21,27,28,31,35,36].

References

(1.) Barkin RL, Lubenow TR, Bruehl S, et al: Management of chronic pain. Part I. Dis Mon 1996; 42:389-454

(2.) Barkin RL, Lubenow TR, Bruehl S, et al: Management of chronic pain. Part II. Dis Mon 1996; 42:457-507

(3.) Barkin RL, Oetgen J, Barkin SJ: Pharmacotherapeutic management opportunities utilized in chronic nonmalignant pain. Supplement to Drug Topics. Montvale, NJ, Medical Economics Publishers, 1999

(4.) Schwer WA, Barkin RL, Katz WA, et al: The Management of Chronic Pain in the Elderly. Langhorne, Pa, Medical Communications Inc, 2000

(5.) McCarberg BH, Barkin RL: Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther 2001; 8:181-186

(6.) Barkin RL: Pharmacotherapy for nonmalignant pain (Letter) . Am Fam Phys 2001; 63:848

(7.) Barkin RL, Schwer WA, Barkin SJ: Recognition and management of depression in primary care: a focus on the elderly. a pharmacotherapeutic overview of the selection process among the traditional and new antidepressants. Amf Ther 2000; 7:205-226

(8.) Barkin RL, Fawcett J: The management challenges of chronic pain: the role of antidepressants. Am J Ther 2000; 7:31-47

(9.) Barkin RL, Barkin DS: Pharmacotherapeutic challenges in the elderly: polypharmacy, drug interactions, compliance and side effects/adverse-effects predictions. Anesth Today 1998; 9:12-19

(10.) Barkin RL, Chor PN, Braun BG, et al: A trilogy case review highlighting the clinical and pharmacologic applications of mirtazapine in reducing polypharmacy for anxiety, agitation, insomnia, depression, and sexual dysfunction. primary care companion. J Clin Psychiatry 1999; 1:172-175

(11.) Barkin RL, Barkin DS, Barkin SJ, et al: Opiate, opioids, and centrally acting analgesics and drug interactions: the emerging role of the psychiatrist. emergency medicine update. Medical Update for Psychiatrists 1998; 3:196-202

(12.) Barkin RL, Sable KS: Caution recommended for prescribing and administering COX 1/COX 2 and COX 2 specific NSAIDs. Pharmacol Ther 2000; 25:196-202

(13.) Gaynes BL, Barkin RL: Analgesics in ophthalmic practice: a review of the oral non-narcotic agent tramadol. Optom Vis Sci 1999; 76:455-461

(14.) Barkin RL: Three challenging, diverse pain patients' requirements for patient-specific treatment, economic and therapeutic implications of analgesia in hospital pharmacy. (Poster presentation) Annual Meeting, American Society of Hospital Pharmacists, Atlanta, Ga, December 8, 1997

(15.) Barkin RL: Focus on tramadol: a centrally acting analgesic for moderate to moderately severe pain. Analgesic Dig 1996;1:11-12

(16.) Barkin RL: Cancer pain treatment insights. Pharmacotherapy 1997; 17:397-398

(17.) Barkin RL: Focus on tramadol: a centrally acting analgesic for moderate to moderately severe pain. Formulary 1995; 30:321-325

(18.) Barkin RL: Alternative dosing for tramadol aids effectiveness. Formulary 1995; 30:542-543

(19.) Huff J, Barkin RL, Lagatuta F: A primary care clinician's and consultant's guide to medicating for pain and anxiety associated with outpatient procedures. Am J Ther 1994; 1:186-190

(20.) Loh VT, Barkin RL: Appropriate use of opiates/opioids in migraine headache pain management. Continuing Pharmacy Education Monograph, Princeton, NJ, Bristol-Myers Squibb Co, 1998, pp 1-28

(21.) Barkin RL, Richtsmeier AY: Alternative agents in pharmacologic management of sickle cell pain crisis complicated by acute pancreatitis. Am J Ther 1995; 2:819-823

(22.) Leiken J, Barkin RL: Nalbuphine vs meperidine in sickle cell anemia DICP. Ann Pharmacother 1990; 24:781-782

(23.) Barkin RL: Pain management update: IV. Morphine infusions in children. Resident Staff Phys 1988; 34:11-13

(24.) Richtsmeier A, Barnes SD, Barkin RL: Ventilatory arrest with morphine patient-controlled anesthesia in a child with renal failure. Am J Ther 1997; 4:255-257

(25.) Hahn A, Oestreich S, Barkin RL: Pharmacology in Nursing. St. Louis, CV Mosby Co, 16th Ed, 1986

(26.) Barkin RL: Withdrawal syndrome is not precipitated when butorphanol is added to opiate or opioid therapy. a comment on intranasal butorphanol-induced apraxia reversed by naloxone. Pharmacotherapy 1996; 16:969

(27.) Bone RC, Hayden WR, Levine RL, et al: Recognition, assessment and treatment of anxiety in the critical care patient. Dis Mon 1995; 41:293-359

(28.) Barkin RL, Braun BG, Kluft RP: The dilemma of drug therapy for multiple personality disorder patients. Treatment of Multiple Peronality Disorders. Braun BG (ed) . Washington, DC, American Psychiatric Press, 1986, pp 107-132

(29.) Braverman B, O'Connor C, Barkin RL: Pharmacology, physiology and anesthetic management of antidepressants. Pharmacology and Physiology in Anesthesia. Philadelphia, Lippincott Health Care Publications, 1993, pp 1-15

(30.) Fawcett J, Barkin RL: Efficacy issues with antidepressants. J Clin Psychiatry 1997; 58 (suppl 6) :32-39

(31.) Bhatia S, Bhatia S, Barkin R: Mirtazapine revisited (Letter) . Am Fam Phys 1997; 56:2190-2192

(32.) Fawcett J, Barkin RL: A meta-analysis of eight randomized, double-blind, controlled clinical trials of mirtazapine for the treatment of patients with major depression and symptoms of anxiety. J Clin Psychiatry 1998; 59:123-127

(33.) Davis J, Barkin RL: Clinical pharmacology of mirtazapine: revisited (Letter) . Am Fam Phys 1999; 60:1101

(34.) Fawcett J, Barkin RL: Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depresson. J Affect Disord 1998; 51:267-285

(35.) Barkin RL, Leikin JB, Barkin SJ: Noncardiac chest pain: a focus upon psychogenic causes. Am J Ther 1994; 1:321-326

(36.) Richtsmeier HA, Barkin RL, Alexander M: Benzodiazepines for acute pain in children. J Pain Symptom Manage 1992; 7:492-495

TABLE. Pharmacokinetics of COX-2 Inhibitors
                                  Celecoxib
Bioavailability                   NA
[T.sub.max] median (hr)           -2.8
[C.sub.max] ([micro]g/mL)         0.7 ([greater than]65 yr, 40%
                                  higher)
AUC ([micro]g/hr/mL)              6.3 (40% increase in black patients
                                   and 50% increase in patients
                                   [greater than or euqal to] 65 yr)
Volume of distribution at steady
 state (L/kg)                     400
Plasma protein binding
 (%)                              -97
Concentration at steady state     [greater than or equal to]5
 (days)
Elimination half-life (hr)        11.2 (fasting state)
GYP-45O substrate hepatic         2C9
 metabolism
Inhibition of hepatic CYP-450     2D6
Metabolism                        Oxidation
Elimination by urine (%)          27
Elimination by feces (%)          57
Sulfonamide allergy               Yes
Dosages
 Osteoarthritis                   200 mg/day or 100 mg twice daily
 Rheumatoid arthritis             100 or 200 mg twice daily
 Acute pain and primary           -
  dysmenorrhea
 Familial adenomatous polyposis   200 mg twice daily
                                  Rofecoxib
Bioavailability                   93%
[T.sub.max] median (hr)           2.0-3.0
[C.sub.max] ([micro]g/mL)
                                  0.2
AUC ([micro]g/hr/mL)
                                  3.3
Volume of distribution at steady
 state (L/kg)                     91
Plasma protein binding
 (%)                              87
Concentration at steady state     4
 (days)
Elimination half-life (hr)        17
GYP-45O substrate hepatic         None
 metabolism
Inhibition of hepatic CYP-450     None
Metabolism                        Reduction (extrahepatic)
Elimination by urine (%)          72
Elimination by feces (%)          14
Sulfonamide allergy               None
Dosages
 Osteoarthritis                   12.5 mg/day; increase
                                   to 25 mg in PM
 Rheumatoid arthritis             -
 Acute pain and primary           50 mg/day; additional dose
  dysmenorrhea                     of 50 mg/day PM
 Familial adenomatous polyposis   -
COX-2 = Cyclooxygenase-2; NA = not applicable; [T.sub.max] =
time to maximum concentration; [C.sub.max] = maximum serum
concentration; AUC = area under the curve; CYP-450 = cytochrome
P-450.
Adapted from Barkin and Sable. [12]
APPENDIX: Pharmacotherapeutic Inhibitors, Inducers, and
Substrates of Cytochrome P-450 (CYP-450) Enzyme With a
Focus on Agents Used in Pain Management
Xenobiotic
CYP-450 Enzyme      Inhibitor
IA2
  Polymorphism: No  Anastrozole
                    Cimetidine
                    Ciprofloxacin
                    Citalopram
                    Clarithromycin
                    Diethyldithiocarbamate
                    Diltiazem
                    Enoxacin
                    Erythromycin
                    Fluoroquinolones
                    Fluvoxamine
                    Grapefruit juice
                     (6',7'-dihydroxybergamotin)
                    Grepafloxacin
                    Isoniazid (INH)
                    Ketoconazole
                    Levofloxacin
                    Mexiletine
                    Mibefradil
                    Mirtazapine (very weak)
                    Moclobemide
                    Nalidixic acid
                    Norfloxacin
                    Omeprazole
                    Paroxetine
                    Propranolol
                    Ritonavir
                    Sertraline
                    Tacrine
                    Zileuton
IIA6
                    Diethyldithiocarbamate
                    Ketoconazole
                    Letrozole
                    Methoxsalen
                    Miconazole
                    Pilocarpine
                    Ritonavir
IIB6
                    Diethyldithiocarbamate
                    Ketoconazole
                    Orphenadrine
                    Quinidine
Xenobiotic
CYP-450 Enzyme      Inducer
IA2
  Polymorphism: No  Bupropion (possible)
                    Caffeine
                    Carbamazepine (CBZ)
                    Charcoal-broiled foods
                    Cigarette smoke
                    Cruciferous vegetable
                    Dihydralazine
                    Omeprazole
                    Phenobarbital
                    Phenytoin
                    Primidone
                    Rifampin
                    Ritonavir
IIA6
IIB6
                    Bupropion (possible)
                    Carbamazepine (CBZ)
                    Phenobarbital
                    Phenytoin
                    Primidone
Xenobiotic
CYP-450 Enzyme      Substrate
IA2
  Polymorphism: No  Acetaminophen (APAP)
                    Antipyrine
                    Bupropion (possible)
                    Caffeine
                    Chlorzoxazone
                    Clozapine
                    Cyclobenzaprine (demethylation)
                    Dantrolene
                    Diazepam
                    Diethylstilbestrol (DES)
                    Estradiol
                    Flutamide
                    Fluvoxamine
                    Grepafloxacin
                    Haloperidol
                    Isotretinoin
                    Lidocaine
                    Methadone
                    Mexiletine
                    Mirtazapine
                    Naproxen
                    Olanzapine
                    Ondansetron
                    Phenacetin
                    Phenothiazines
                    Pramipexole
                    Procarbazine
                    Propafenone
                    Propranolol
                    Prostaglandins
                    Riluzole
                    Ritonavir
                    Ropinirole
                    Ropivacaine
                    Tacrine
                    Tamoxifen
                    Testosterone
                    Theophylline
                    Tiagabine
                    TCAs (N-demethylation)
                     Amitriptyline
                     Clomipramine
                     Desipramine
                     Imipramine
                     Nortriptyline
                    Verapamil
                    Warfarin (R form)
                    Zileuton
                    Zolpidem
IIA6
                    Letrozole
                    Nicotine
                    Ritonavir
                    Tamoxifen
IIB6
                    Bupropion
                    Cyclophosphamide
                    Diazepam (demethylation)
                    Halothane
                    Ifosfamide
                    Mianserin
                    Mephenytoin (S-isomer
                     demethylated)
                    Tamoxifen
                    Temazepam
IIC8, IIC9, IIC1O
  Polymorphism: Yes              Anastrozole (2C8/2C9)
  (poor metabolizers);           Amiodarone (2C9)
  [greater than or equal to]20%  Cannabinols
  Whites,
  2% Asians,                     Chloramphenicol (2C9)
  2% African Americans           Cimetidine (2C9)
                                 Clopidogrel (2C9)
                                 Delavirdine
                                 Diclofenac (2C9)
                                 Diethyldithiocarbamate (2C8)
                                 Disulfiram (2C9)
                                 Efavirenz (2C9)
                                 Felbamate (2C8)
                                 Fluconazole (2C9)
                                 Fluoxetine (suspected) (2C9)
                                 Flurbiprofen (2C9)
                                 Fluvastatin (2C9)
                                 Fluvoxamine (2C9)
                                 Isoniazid (INH)
                                 Ketoconazole
                                 Ketoprofen (2C9)
                                 Leflunomide
                                 Metronidazole (2C9)
                                 Miconazole (2C9)
                                 Omeprazole (2C8/2C9)
                                 Phenylbutazone (2C9)
                                 Ritonavir (2C9, 2C1O)
                                 Sertraline (suspected)
                                 Sulfonamides (2C9)
                                 Topiramate
                                 Trimethoprim/sulfamethiazole
                                   (TMP/SMX) (2C9)
                                 Troglitazone (2C9)
                                 Zafirlukast (2C9)
IIC18-19
  Polymorphism:                  Cimetidine (2C18)
  Yes (2C19);                    Citalopram (2C19)
  18% Japanese,                  Delavirdine
  20% African Americans,         Efavirenz (2C19)
  20% Asians,                    Felbamate (2C19)
  3%-5% Whites                   Fluoxetine (2C19)
IIC8, IIC9, IIC1O
  Polymorphism: Yes              Barbiturates
  (poor metabolizers);           Bupropion (possible)
  [greater than or equal to]20%  Carbamazepine (2C9) (CBZ)
  Whites,
  2% Asians,                     Clopidogrel (2C9)
  2% African Americans           Dexamethasone
                                 Ethanol (2C9)
                                 Phenobarbital (2C9)
                                 Phenytoin (2C9)
                                 Rifampin (2C9)
                                 Rifapentine (2C8/2C9)
IIC18-19
  Polymorphism:                  Bupropion (possible)
  Yes (2C19);                    Rifampin (2C19)
  18% Japanese,
  20% African Americans,
  20% Asians,
  3%-5% Whites
IIC8, IIC9, IIC1O
  Polymorphism: Yes              Amitriptyline (2C9)
  (poor metabolizers);           Aspirin (ASA)
  [greater than or equal to]20%  Barbiturates (2C9)
  Whites,
  2% Asians,                     Benzphetamine (2C8)
  2% African Americans           Bupropion
                                 Carbamazepine (CBZ)
                                 Carvedilol (2C9)
                                 Celecoxib (2C9)
                                 Clomipramine (2C9)
                                 Cyclophosphamide
                                 Dapsone (2C9)
                                 Delavirdine (2C9)
                                 Diazepam (2C8/2C9)
                                 Diclofenac (2C8/2C9)
                                 Donepezil
                                 Dronabinol (2C9)
                                 Efavirenz (2C9)
                                 Ethosuximide
                                 Flurazepam
                                 Flurbiprofen (2C9)
                                 Fluoxetine (2C9)
                                 Fluvastatin (2C9)
                                 Glimepiride (2C9)
                                 Glipizide
                                 Glyburide
                                 Hexobarbital (2C9)
                                 Ibuprofen (2C9)
                                 Imipramine (2C8/2C9)
                                 Indomethacin (2C8/2C9)
                                 Irbestartan
                                 Isotretinoin (2C8)
                                 Lansoprazole
                                 Leflunomide (2C9)
                                 Losartan (2C9)
                                 Mefenamic acid (2C9)
                                 Mephenytoin (2C9)
                                 Mephobarbital (2C9)
                                 Mirtazapine (2C9)
                                 Montelukast (2C9)
                                 Naproxen (2C9)
                                 Nifedipine
                                 NSAIDs (2C9)
                                 Omeprazole (2C8)
                                 Paclitaxel (2C8)
                                 Phenytoin (2C9)
                                 Piroxicam (2C9)
                                 Propranolol
                                 Retinoic acid (2C8)
                                 Ritonavir (2C9)
                                 Sildenafil (2C9, minor)
                                 Sulfonamide (including celecoxib)
                                 Tamoxifen (2C9)
                                 TCAs (tertiary amines) (2C9)
                                 Terbinafine (2C9)
                                 Tetrahydrocannabinol ([delta]THC)
                                 (2C9)
                                 Tolbutamide (2C8/2C9)
                                 Tolcapone
                                 Torsemide (2C9)
                                 Valproic acid
                                 Warfarin S-form (more active) (2C9)
                                 Zafirlukast (2C9)
                                 Zileuton (2C9)
IIC18-19
  Polymorphism:                  Amitriptyline (2C19)
  Yes (2C19);                    Barbiturates (2C19)
  18% Japanese,                  Carisoprodol (2C19)
  20% African Americans,         Carvedilol
  20% Asians,                    Citalopram (minor) (2C19)
  3%-5% Whites                   Clomipramine (2C19)
                             Fluvoxxamine (2C19)
                             Ketoconazole
                             Letrozole
                             Omeprazole (2C19)
                             Oxcarbazepine (2C19)
                             Ritonavir (2C19)
                             Telmisartan (2C19)
                             Topiramate (2C19) minor
                             Tolbutamide (2C19)
                             Tranylcypromine (2C19)
                             Troglitazone (2C19)
IID6
   Subject to genetic        Amiodarone               None
   Polymorphism sublet       Amitriptyline
   Of 5%-10% of Whites,      Bupropion
   1%-10% Asians;            Celecoxib
   2%-8% African Americans:  Chloroquine
   Poor metabolizers or      Cimetidine
   Deficits in activity      Citalopram (weak)
                             Clomipramine
                             Codeine
                             Delavirdine
                             Desipramine
                             Dextropropoxyphene
                             Diphenhydramine
                             Doxorubicin
                             Fenfluramine
                             Flecainide
                             Fluoxetine
                             Fluphenazine
                             Fluvoxamine
                             Haloperidol
                             Imipramine
                             Lomustine
                             Methadone
                             Metoprolol
                             Mexiletine
                             Mibefradil
                             Mirtazapine (very weak)
                             Moclobemide
                             Nicardipine
                             Norfluvoxamine
                             Norfluoxetine
                             Nortriptyline
                             Parpxetine
                             Perphenazine
                             Primaquine
                             Propafenone
                             Propafenone
                             Propoxyphene
                             Quinidine
                             Ranitidine
                             Ritonavir
                             Sertraline (suspected)
                             TCAs
                             Thioridazine
                             Diazepam (2C19)
                             Divalproex sodium VPA (2C19)
                             Hexobarbital (2C19)
                             Irbesatan
                             Imipramine (2C19)
                             Lamsoprazole (2C19)
                             Moclobemide (N-demethylation)
                             Omeprazole (2C19)
                             Naproxen (2C18)
                             Nordazepam (2C19)
                             Pantoprazole (2C19)
                             Phenytoin
                             Piroxicam (2C18)
                             Propranolol (2C19)
                             Retinoic acid (2C18)
                             Ritonavir (2C19)
                             Tertiary amines TCA (2C19)
                             Tiagabine
                             Tolbutamide (2C19)
                             Topirmate
                             Valproate VPA (2C19)
                             Valproic acid (2C19)
                             Tetrahydrocannabinol ([detla]THC)
                               S-isomer (2C18)
                             Warfarin S-isomer (2C18)
IID6
   Subject to genetic        Amiodarone
   Polymorphism sublet       Antidysrhythmics, type IC
   Of 5%-10% of Whites,      [beta]-A Adrenergic blockers (some)
   1%-10% Asians;            Bisoprolol
   2%-8% African Americans:  Bupropion
   Poor metabolizers or      Captopril
   Deficits in activity      Carvedilol
                             Chloroquine
                             Chlorpeniramine
                             Chlorpormazine
                             Citalopram (minor)
                             Clomipramine
                             Clozapine
                             Codeine
                             Cyclobenzaprine (hydroxylation)
                             Debrisoquine
                             Delavirdine
                             Dexfenfluramine
                             Dextromethorphan (DM)
                             Dolasertron
                             Donepezil
                             Encainide
                             Ethylmorphine
                             Fenfluramine
                             Flecainide
                             Fluozetine
                             Fluphenazine
                             Fluvoxamine
                             Halofantrine
                             Haloperidol
                             Hydrocodone
                             Hydroxyamphetamine
                             Labetalol
                             Lansoprazole
                             Lidocaine
                             Loratadine
                             Maprotiline
                             MCPP (metabolite of
                               trazodone & nefazodone)
                             Meperidine
                             Methadone
                             Methamphetamine
                             Metoprolo (R&S enantiomers)
                             Mexiletine
                     Timolol
                     Venlafaxine (very weak)
                     Vinblastine
                     Vinorelbine
                     Yohimbine
                     Ziprasidone
IIE1
  Polymorphism: Yes  Diethyldithiocarbamate   Ethanol (ETOH)
                     Disulfiram               Isoniazid (INH)
                     Ritonavir
IIA1
                                              Spironolactone
                     Mirtazapine
                     Morphine (major pathway
                      phase II glucuronidation
                      to M-6-G and M-3-G)
                     Neuroleptics
                     Nicotine
                     Nortriptyline
                     Olanzipine
                     Omeprazole
                     Ondansetron
                     Opiate analgesics
                     Oxamniquine
                     Oxycodone
                     Paroxetine
                     Pentazocine
                     Perphenazine
                     Phenformin
                     Phenothiazines
                     Pindolol
                     Primaquine
                     Proguanil
                     Propafenone
                     Propoxyphene
                     Propranolol (minor)
                     Risperidone
                     Ritonavir
                     Ropivacaine
                     Selegiline
                     Sertraline
                     Sparteine
                     Tamoxifen
                     TCAs (hydroxylation/high
                      first-pass effeccs)
                      Amitriptyline
                      Clomipramine
                      Desipramine
                      Doxepin
                      Imipramine
                      Nortriptyline
                     Thebaine
                     Tiagabine
                     Timolol
                     Tolterodine
                     Tramadol (M1 metabolite zone)
                     Trazodone
                     Trimipramine
                     Venlafaxine
                     Zolpidem
                     Zonisamide
IIE1
  Polymorphism: Yes  Acetaminophen (hepatotoxic
                      metabolite-NAPQI)
                     Benzene
                     Bupropion
                     Carbon tetrachloride
                     Chlorzoxazone
                     Dapsone
                     Enflurane
                     Ethanol (minor)
                     Halothane
                     Isoflurane
                     Isoniazid (INH)
                     Methoxyflurane
                     Mexiletine
                     Mirtazapine (minor)
                     Ondansetron
                     Ritonavir
                     Sevoflurane
                     Tamoxifen
                     Theophylline
IIA1
IIIA3
                               Cimetidine
                               Nefazodone
                               Ranitidine
                               Sertraline
IIIA4
  Polymorphism: No             Acetaminophen (APAP)
  (Significant differences in  Amiodarone
  CYPIII A4 expression         Anastrozole
  among patients)              Antibiotics
                               Calcium channel
                                 blockers (some)
                               Cannabinol
                               Cimetidine
                               Clarithromycin
                               Clotrimazole
                               Danazol
                               Delavirdine
                               Dextropropoxyphene
                               Diethyldithiocarbamate
                               Dihydroergotamine (DHE)
                               Diltiazem
                               Efavirenz
                               Erythromycin
                               Ethinyl-estradiol
                               Fluconazole
                               Fluoxetine
                               Fluvoxamine
                               Gestagen
                               Grapefruit juice
                                 (6,7-dihydroxybergamotin)
                               Indinavir
                               Interferon-y
                               Itraconazole
                               Ketoconazole
                               Lovastatin
                               Macrolide antibiotics
                               Metronidazole
                               Mibefradil
                               Miconazole
                               Mirtazapine (very weak)
                               Naringerin
                               Nefazodone
                               Nelfinavir
                               Nevirapine
                               Nifedipine
                               Norfloxacin
                               Norfluoxetine
                               Omeprazole
                               Paroxetine
                               Propanolol
                               Propoxyphene
                               Quinidine
                               Quinine
                               Ranitidine
                               Ritonavir
                               Saquinavir
                               Sertraline
                               Troglitazone
                               Trolcandomycin
                               Verapamil
                               Zafirlukast
                               Ziprasidone
IIIA3
                               Erythromycin
IIIA4
  Polymorphism: No             Aconiazide
  (Significant differences in  Barbiturates
  CYPIII A4 expression         Carbamazepine (CBZ)
  among patients)              Dexamethasone
                               Efavirenz
                               Ethosuximide
                               Glucocorticoids
                               Griseofulvin
                               Macrolide antibiotics
                               Nevirapine
                               Oxcarbazpine
                               Phenobarbital
                               Phenylbutazone
                               Phenytoin (PHT)
                               Prednisone
                               Primidone
                               Quinidine
                               Rifabutin
                               Rifampicin
                               Rifampin
                               Rifapentine
                               Sulfinpyrazone
                               Troglitazone
                               Verapamil
IIIA3
                               Midazolam
IIIA4
  Polymorphism: No             Acetaminophen (APAP)
  (Significant differences in  Alfentanil
  CYPIII A4 expression         Alprazolam
  among patients)              Amiodarone
                               Amlodipine
                               Androgens
                               Antiarrhythmics
                               Astemizole
                               Atorvastatin
                               Azithromycin
                               Azole antifungals
                               Benzndiazepincs (short-acting
                                 triazole type)
                               Benzphetamine
                               Bromocriptine
                               Bupropion (possible)
                               Busulfan
                               Caffeine
                               Calcium channel
                                 blockers (most)
                               Cannabinol ([delta]THC)
                               Carbamazepine (CBZ)
                               Carvedilol
                               Cerivastatin
                               Chlorpromazine
                               Cisapride
                               Citalopram
                               Clarithromycin
                               Clindamycin
                               Clonazepam
                               Clotrimazole
                               Clozapine
                               Cocaine
                               Codeine (demethylation)
                               Corticosteroids
                               Cortisol
                               Cyclobenzaprine
                                 (demethylation)
                               Cyclophosphamide
                               Cyclosporine (CSP)
                               Dantrolene
                               Dapsone
                               Delavirdine
                               Dexametbasone
                               Dextromethorphan (DM)
                               Diazepam (minor)
                               Digitoxin
                               Digoxin
                               Dihydroergotamine (DHE)
                               Dihydropteridine calcium
                                 channel blockers
                               Diltiazem
                               Disopyramide
                               Docetaxel
                               Dolasetron
                               Domperidone
                               Donepezil
                               Doxorubicin
                               Dronabinol
                               Enalapril
                               Erythromycin
                               Estradiol
                               Estrogens (oral contraceptives)
                               Ethinyl estradiol
                               Ethosuximide
Xenobiotic
CYP-450 Enzyme  Inhibitor  Inducer
                                    Ethylmorphine
                                    Etoposide
                                    Felodipine
                                    Fentanyl
                                    Fexofenadine
                                    Fluoxetine
                                    Flutamide
                                    Fluvoxamine
                                    Glyceryl trinitrate
                                    Granisetron
                                    Grepafloxacin
                                    Halofantrine
                                    Haloperidol
                                    Hydrocortisone (cortisol)
                                    Irbesartan
                                    Ifosfamide
                                    Indinavir
                                    Isradipine
                                    Ketoconazole
                                    Lansoprazole (minor)
                                    Letrozole
                                    Lidocaine
                                    Lorasadine
                                    Losartan
                                    Macrolide antibiotics
                                    Mephenytoin
                                    Metronidazole
                                    Mibefradil
                                    Miconazole
                                    Midazolam (3A5)
                                    Mifepristone
                                    Mirtazapine
                                    Montelukast
                                    Navelbine
                                    Nefazodone
                                    Nelfinavir
                                    Nevirapine
                                    Nicardipine
                                    Nifedipine
                                    Nimodipine
                                    Nisoldipine
                                    Nitrendipine
                                    Omeprazole
                                    Ondansetron
                                    Paclitaxel
                                    Pantoprazole
                                    Phenobarbital
                                    Phenytoin (PHT)
                                    Pimozide
                                    Pravastatin
                                    Prednisone
                                    Primidone
                                    Progesterone
                                    Propafenone
                                    Protease inhibitor (HIV-1)
                                    Quetiapine
                                    Quinine
                                    Retinoic acid
                                    Rifampin
                                    Ritonavir
                                    Ropivacaine
                                    RU 486
                                    Salmeterol
                                    Saquinavir
                                    Sertindole
                                    Sertraline
                                    Sibutramine
                                    Sildenafil
                                    Simvastatin
                                    Sufentanil
                                    Tacrolimus (FK506)
III A5-7
          Clotrimazole    Phenobarbital
          Ketoconazole    Phenytoin (PHT)
          Metronidazole   Primidone
          Miconazole      Rifampin
          Troleandomycin
          Tamoxifen
          TCAs (demethylation)
            Amitriptyline (minor)
            Clomipramine
            Imipramine
          Teniposide
          Terfenadine
          Testosterone
          Theophylline
          Thiothixene
          Tiagabine
          Tolterodine
          Toremifene
          Tramadol (Ml metabolite)
          Trazodone
          Tretinoin
          Triazolam
          Troglitazone
          Troleandomycin
          Venlafaxine (N-demethylation)
          Verapamil
          Vinbiastine
          Vincristine
          Vindesine
          Warfarin (less active, R form)
          Zileuton
          Zolpidem
          Zonisamide
III A5-7
          Ethinyloestradiol
          Lovastatin (3A5)
          Midazolam (3A5)
          Nifedipine (3A5)
          Quinidine
          Terfenadine
          Testosterone
          Triazolam
          Vinblastine
          Vincristine
TCA = Tricyclic antidepresant; ASA = acetylsalicylic acid; NSAID =
nonsteroidal anti-inflammatory drug; VPA = valproic acid; mCPP =
metacholorophenyl piperazine; m-6-G = morphine-6-glucuronider; M-3-G =
morphine-3-glucuronide; HIV-1 = human immunodeficiency virus-1.