Drugs Aging 2010; 27 (5): 417-433 1170-229X/10/0005-0417/$49.95/0

THERAPY IN PRACTICE

ª 2010 Adis Data Information BV. All rights reserved.

Implications of Opioid Analgesia for Medically Complicated Patients Howard Smith1 and Patricia Bruckenthal2 1 Department of Anesthesiology, Albany Medical College, Albany, New York, USA 2 Stony Brook University School of Nursing, Stony Brook, New York, USA

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Literature Search Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Polypharmacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Renal Impairment/Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Hepatic Impairment/Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Cardio/Respiratory Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Cerebrovascular Disease, Dementia and Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Limited Routes of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Psychiatric Illness and Addiction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 Who is at Risk? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 What are the Consequences for Opioid Selection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

417 419 419 419 420 420 420 421 423 423 423 423 423 424 425 425 425 425 425 426 426 426 427 428

Opioid analgesics have an established role in the management of postoperative pain and cancer pain, and are gaining acceptance for the management of moderate to severe chronic noncancer pain, most notably chronic low back pain and osteoarthritis, that does not respond to other interventions. Many patients with chronic pain have co-morbid medical conditions that may complicate opioid therapy. Selecting the appropriate opioid requires knowledge of how individual opioids differ with respect to metabolism and interaction with concurrent medications, as well as the reasons why specific medical conditions may influence their efficacy and tolerability. Polypharmacy is a common complicating condition in the elderly and in patients with psychiatric illness, cancer, cardiovascular disease, diabetes

Smith & Bruckenthal

418

mellitus or other chronic illnesses. Polypharmacy, though often necessary for patients with multiple medical conditions, also multiplies the risk of drug interactions. Pharmacokinetic drug interactions can increase or reduce exposure to the opioid or concurrent medications, reducing efficacy and/or tolerability and increasing toxicity. Pharmacodynamic interactions can enhance the depressive effects of opioids, compromising safety. Patients with impaired renal or hepatic function may have difficulty clearing or metabolizing opioids and concurrent medications, leading to increased risk of adverse events. Patients with cardiovascular, cerebrovascular or respiratory disease (including smokers of ‡2 packs/day with no other diagnosis) may be more susceptible to respiratory depression, bradycardia and hypotension with any opioid, and a few specific opioids pose additional risks. Patients with cerebrovascular disease, dementia, brain injury or psychiatric illness are more susceptible to opioid effects on the CNS, which can include euphoria, cognitive impairment and sedation. Appropriate opioid selection may mitigate these effects. Even in older patients, addiction, abuse and misdirection of prescribed opioids are of concern. Higher risk exists for patients with psychiatric illness, history of substance abuse, and identifiable substance abuse risk factors. Screening for abuse potential and vigilant patient monitoring should be routine. Opioids differ in their ability to produce euphoria, based on opioid receptor agonism, but substance abusers may be more influenced by availability, familiarity and cost factors. Consequently, opioid selection has limited influence on abuse potential but can facilitate ease of monitoring. This review provides an overview of opioid use in medically complicated patients and recommendations on how to optimize analgesia while avoiding adverse events and drug interactions in the clinical setting. Articles cited in this review were identified via a search of EMBASE and PubMed. Articles selected for inclusion discussed characteristics of specific opioids and general physiological aspects of opioid therapy in important patient populations.

Opioid analgesics remain an important treatment option for the management of postoperative[1] and cancer pain,[2,3] and have been gaining acceptance in the management of chronic noncancer pain,[4] including chronic lower back pain[5] and osteoarthritis pain,[6] that does not respond adequately to other treatments. In 2009, the American Pain Society and the American Academy of Pain Medicine issued joint guidelines recommending the judicious use of opioid analgesics when chronic noncancer pain is moderate or severe, when it has an adverse effect on function or quality of life, and when a careful risk-benefit assessment indicates a likely net benefit.[7] Also in 2009, the American Geriatric Society issued guidelines on persistent pain in the elderly, which place opioids as a second-line choice for pain management after paracetamol ª 2010 Adis Data Information BV. All rights reserved.

(acetaminophen), and state that ‘‘all patients with moderate-severe pain, pain-related functional impairment or diminished quality of life due to pain should be considered for opioid therapy.’’[8] International guidelines for the management of arthritis also consider opioid analgesics a potential option for pain that does not respond to oral paracetamol or to oral or topical NSAIDs.[9,10] Consistent with these recommendations, recent surveys and reviews indicate that opioid analgesics are now commonly prescribed to patients with chronic noncancer pain conditions such as osteoarthritis and low back pain,[11,12] presumably providing benefits outweighing the risk of adverse events and addiction. Although opioids have demonstrated efficacy in clinical trials,[13] prescribing opioids in clinical practice is more complicated. Many patients with Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

acute or chronic pain requiring opioid analgesia are in poor health, with a high prevalence of comorbid conditions such as cancer, asthma and other respiratory problems, diabetes mellitus, hypertension and cardiovascular disease, renal or hepatic impairment, cerebrovascular disease and neurological disease.[12] These conditions and the medications prescribed to manage them can greatly complicate opioid therapy. Commonly used opioid analgesics in the US include hydrocodone/paracetamol, oxycodone, oxycodone/paracetamol, codeine/paracetamol, methadone, fentanyl, morphine and oxymorphone.[14,15] Tramadol is also available for the management of chronic pain. Although considered an opioid, tramadol is actually a partial m-opioid receptor agonist that exerts roughly 70% of its analgesic effects through noradrenaline (norepinephrine) and serotonin reuptake inhibition.[16] The most recent entrant to the opioid market, tapentadol, is also a weak agonist at the m-opioid receptor and an inhibitor of both noradrenaline and serotonin reuptake.[17] Pethidine (meperidine) and dextropropoxyphene (propoxyphene) are also available and, unfortunately, are used extensively in the elderly even though they are both considered unsuitable for geriatric use according to the Beers criteria.[18] Judicious selection of an opioid analgesic from among these agents requires knowledge of the likelihood that a selected agent will be effective and tolerated and not worsen the clinical situation of the patient. Prescribers need to consider the patient’s concurrent medications, co-morbid medical conditions and risk factors, including risk factors for or history of substance abuse. In addition, patients vary significantly in their response to individual opioids,[19,20] frequently requiring multiple trials of ostensibly similar opioids in order to find an option that is effective and sufficiently well tolerated. Some patients who have been treated successfully with opioids may develop analgesic tolerance to treatment and require rotation to a substitute opioid to maintain analgesia or avoid adverse events that can occur with dose escalation. For these reasons, practitioners will need to be comfortable using multiple opioid analgesics in clinically diverse patients. ª 2010 Adis Data Information BV. All rights reserved.

419

This review provides an overview of common clinical situations that define the medically complicated patient and consequent considerations in selecting an appropriate opioid. 1. Literature Search Methodology Articles cited in this review were identified via a search of EMBASE and PubMed for literature published between January 1980 and January 2010. The opioid medication search terms used were as follows: ‘codeine’, ‘fentanyl’, ‘hydrocodone’, ‘hydromorphone’, ‘methadone’, ‘morphine’, ‘opioid’, ‘opioid analgesic’, ‘oxycodone’, ‘oxymorphone’, ‘tapentadol’ and ‘tramadol’. Each medication search term was combined with the following general search terms: ‘active metabolites’, ‘addiction’, ‘adverse effects’, ‘safety OR toxicity’, ‘cardiovascular disease’, ‘cerebrovascular disease’, ‘dementia OR brain injury’, ‘drug interactions’, ‘formulations’, ‘hepatic impairment’, ‘pharmacokinetics’, ‘pharmacology’, ‘psychiatric illness’, ‘receptor binding’, ‘receptor’, ‘renal impairment’ and ‘respiratory disease’. The reference lists of relevant papers were examined for additional articles of interest. References were selected for inclusion in the review on the basis of being the most current, accurate and relevant sources to support the development of a practical clinical overview of opioid use for pain management for the medically complicated patient. Preference was given to articles discussing chronic opioid use in the elderly, clinical trials of high quality, reports on opioid safety and adverse events, and both clinical and preclinical research that characterize the mechanisms underlying opioid effects. 2. Polypharmacy 2.1 Who is at Risk?

Polypharmacy (i.e. taking multiple medications, whether clinically appropriate or not) is common among patients with chronic pain requiring opioid analgesia.[21,22] In a populationbased survey, 17% of patients receiving opioid analgesia took two opioids, 32% were receiving more than five concurrent medications, and 21% Drugs Aging 2010; 27 (5)

Smith & Bruckenthal

420

were taking more than ten concurrent medications.[22] Polypharmacy is prevalent in several populations that are commonly prescribed opioids, including the elderly;[22-26] patients with depression, anxiety and other psychiatric comorbidities;[24,27-29] cancer patients;[30] and other patients with multiple medical problems. Unnecessary polypharmacy may occur in elderly patients who express depression and anxiety in terms of somatic complaints.[29] Polypharmacy multiplies the risk of drug-drug interactions (DDIs).[23,25] Clinically important interactions may include pharmacokinetic interactions, which alter the manner in which the body absorbs, metabolizes, distributes or eliminates the drug, and pharmacodynamic interactions, which occur when adding a second drug alters the response to the first, usually because of either antagonistic or additive/synergistic effects on the same biochemical pathway or activity. Pharmacokinetic DDIs can alter exposure to an opioid (or a drug administered concurrently), leading to reduced efficacy, decreased tolerability, or toxicity. Pharmacodynamic DDIs are also a risk with opioids, which may be antagonistic (naloxone),[31] synergistic (a-adrenoceptor agonists)[32] or additive (CNS depressants, alcohol [ethanol]).[33] 2.2 What are the Consequences for Opioid Selection?

Most opioids undergo phase I metabolism mediated by the cytochrome P450 (CYP) enzymes, in particular CYP3A4 and CYP2D6,[34,35] and therefore have significant interaction potential with other drugs that share the same metabolic pathway (table I). CYP3A4 alone is estimated to be involved in the metabolism of >50% of all drugs.[34] The interaction potential of drugs metabolized by CYP3A4 is generally predictable, making clinically relevant interactions also predictable and generally manageable. Fewer drugs are metabolized by CYP2D6, but the potential for adverse events and drug interactions for opioids metabolized by this enzyme are less predictable. Several genetic polymorphisms have been identified that predispose individual patients to excessively slow or rapid ª 2010 Adis Data Information BV. All rights reserved.

metabolism of drugs using this enzyme, resulting in increased or diminished drug concentrations.[36] Altered CYP2D6-mediated metabolism may reduce the efficacy of hydrocodone and the tolerability of codeine,[37,38] both of which are metabolized entirely by CYP2D6. Oxycodone is metabolized primarily by CYP3A4 but also requires CYP2D6 for metabolism to oxymorphone, a minor metabolite.[36] Concurrent administration of oxycodone and quinidine reduces production of oxymorphone from oxycodone.[39] Although reduced production of oxymorphone from oxycodone appears not to be clinically relevant in most patients,[39] there have been individual cases of reduced efficacy[38] and increased toxicity[37] in CYP2D6 poor metabolizers treated with oxycodone. Generally, when the risk of DDIs must be minimized, prescribers are safer selecting an opioid that is not metabolized by the CYP system. Morphine,[40] hydromorphone,[41] oxymorphone[42,43] and tapentadol[44] each undergo phase II hepatic metabolism, but by a process known as glucuronidation. Tapentadol inhibits CYP2D6 activity, but not to an extent considered clinically relevant.[44] Glucuronidation of opioids is mediated by the uridine diphosphate glucuronosyltransferase 2B7 enzyme rather than by CYP enzymes. Drugs that bypass CYP-mediated metabolism have minimal drug interaction potential.[45] 3. Renal Impairment/Failure 3.1 Who is at Risk?

Renal impairment becomes more prevalent with advancing age as the glomerular filtration rate decreases by an estimated mean of 0.75–0.9 mL/min annually after the age of 30–40 years.[46,47] Consequently, an individual aged 80 years can be expected to have approximately two-thirds of the renal function they had at age 20 or 30 years.[46,47] Most opioids are eliminated primarily in urine, making dosage adjustments necessary in patients with renal impairment.[42,48-52] The possibility of renal compromise should be suspected whenever pre-renal, intra-renal, or post-renal risk factors are present. Pre-renal Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

421

Table I. Metabolism and potential drug-drug interactions of common opioid analgesics Opioid

Metabolic pathway

Pharmacokinetic interactions

Pharmacodynamic interactions

Codeine

CYP2D6/glucuronidation

CYP2D6 substrates, inhibitors, and inducersa

Anticoagulants (additive) CNS depressants (additive)

Fentanyl

CYP3A4

CYP3A4 substrates, inhibitors, and inducersb

CNS depressants (additive)

Hydrocodone

CYP2D6/glucuronidation

CYP2D6 substrates, inhibitors, and inducersa

CNS depressants (additive)

Hydromorphone

Glucuronidation via UGT2B7

Minimal interaction potential

CNS depressants (additive)

Methadone

CYP2B6 CYP2C8 CYP2C19 CYP2D6 CYP2C9

CYP substrates, inhibitors, and inducers

Arrhythmogenic agents – class I and II (additive) CNS depressants (additive) TCAs, CCBs, antipsychotics – selected (additive) Diuretics and laxatives

Morphine

Glucuronidation via UGT2B7 CYP2D6

Minimal interaction potential

CNS depressants (additive)

Oxycodone

CYP3A4 CYP2D6

CYP3A4 substrates, inhibitors, and inducersb CYP2D6 substrates, inhibitors, and inducersa

CNS depressants (additive)

Oxymorphone

Glucuronidation via UGT2B7

Minimal interaction potential

CNS depressants (additive)

Tramadol

CYP3A4 CYP2D6 CYP2B6

CYP3A4 substrates, inhibitors, and inducersb CYP2D6 substrates, inhibitors, and inducersa

CNS depressants (additive) SSRIs, SSNRIs, TCAs, MAOIs, cyclobenzaprine and serotonin 5-HT1B/1D receptor agonists (triptans) [additive]

a

Includes antiarrhythmics, antipsychotics, b-adrenoceptor antagonists (b-blockers), celecoxib, histamine H2-receptor antagonists, rifampicin, ritonavir, SSNRIs, SSRIs, tamoxifen and TCAs (for a comprehensive list, see Smith[36]).

b

Includes numerous antibacterials, antiepileptics, antipsychotics, antiretrovirals, azole antifungals, benzodiazepines, CCBs, chemotherapeutics, hormonal therapies, sildenafil, sleep aids, SSRIs, HMG-CoA reductase inhibitors (statins) and warfarin (for a comprehensive list, see Smith[36]).

CCB = calcium channel antagonist (calcium channel blocker); CYP = cytochrome P450; MAOI = monoamine oxidase inhibitor; SSNRI = selective serotonin-noradrenaline reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; UGT = uridine diphosphate glucuronosyltransferase.

insults to the kidney involve hypovolaemia or hypoperfusion, either of which can result from dehydration, sepsis, blood loss, heart failure, liver failure and renal artery obstruction due to trauma, masses or thrombosis.[53] Intra-renal damage can result from kidney disease, trauma, infection and neoplasms as well as hypertension, diabetes and toxins, such as NSAIDs and myoglobin from muscle trauma, ischaemia and burns. Post-renal obstruction due to surgical mishap, trauma, neoplasms, stones and prostate disease may lead to renal failure.[53] Renal impairment of possible pharmacological significance is defined by the US FDA as an estiª 2010 Adis Data Information BV. All rights reserved.

mated creatinine clearance rate <80 mL/min/m2.[54] Moderate and severe renal impairment are present when creatinine clearance is 30–50 and <30 mL/min/m2, respectively. 3.2 What are the Consequences for Opioid Selection?

Dosage adjustments are usually required in patients with renal impairment because most opioids are eliminated in urine.[41,42,50,51] Prescribers should initiate opioid therapy at a low dose, titrate slowly, and monitor drug concentrations and adverse events. Drugs Aging 2010; 27 (5)

Smith & Bruckenthal

422

Practitioners generally should avoid prescribing pethidine to patients with renal impairment because accumulation of its norpethidine metabolite can result in serious neurotoxicity.[55,56] Similarly, dextropropoxyphene should be avoided in this population because accumulation of its nordextropropoxyphene metabolite has been linked to serious cardiac, CNS and respiratory depression.[57] Morphine, hydromorphone, codeine and tramadol should be avoided or used with extreme caution in the renally impaired population. Although morphine clearance is not substantially altered in renal impairment, clearance of morphine-6-glucuronide and morphine-3-glucuronide metabolites is dramatically decreased.[58-61] Accumulation of morphine or its metabolites in patients with renal impairment can produce severe adverse events, which include respiratory depression, sedation, nausea and vomiting,[62-65] and neuroexcitatory effects such as allodynia, myoclonus and seizures.[66] Similarly, in patients with chronic renal failure, administration of hydromorphone 24 mg has been associated with a 4-fold increase in the ratio of the primary metabolite of hydromorphone, hydromorphone3-glucuronide, relative to hydromorphone.[67] Hydromorphone-3-glucuronide has been asso-

ciated with neuroexcitatory symptoms similar to those seen with morphine.[66] In patients with renal impairment treated with codeine, clearance of codeine, codeine glucuronide, morphine and morphine glucuronide is reduced.[68,69] Codeine administration in these patients has been associated with profound hypotension, respiratory depression and narcolepsy; chronic administration would be expected to result in toxic concentrations in two-thirds of dialysis patients.[68] Tramadol extended release (ER) is available in a limited number of dosage strengths, making dosage adjustments difficult. Consequently, use of this opioid in patients with severe renal impairment is contraindicated.[70] In contrast, it appears that methadone and fentanyl may be less affected than other opioids by renal impairment.[71] However, methadone is generally not recommended as a first-line opioid in the elderly because it exhibits highly variable pharmacokinetics and nonlinear dose equivalencies, making transitions to or from other opioids challenging.[8] Regardless of the opioid administered, patients with advanced chronic kidney disease should be started at a low dose and titrated slowly. Table II provides general recommendations for the prescription of opioids in patients with renal impairment.

Table II. Recommendations for prescribing opioids in patients with renal or hepatic failure (adapted by permission from: Informa Healthcare, Journal of Pain & Palliative Care Pharmacotherapy, Murtagh et al.[72] copyright 2007; and Tegeder et al.,[73] with permission from Adis, a Wolters Kluwer business [ª Adis Data Information BV 1999. All rights reserved.]) Recommendation

Renal failure[72]

Hepatic failure[73]

Recommended

Fentanyl

Fentanyl

Recommended with caution

Tramadol

Hydromorphone[41,74]

Methadonea

Morphine Oxycodone[50,75] Methadonea

Not recommended

Limited information available

Codeine

Codeine

Hydrocodone

Oxymorphone[42,76]

Morphine

Tramadol

Buprenorphine

Buprenorphine

Hydromorphone

Hydrocodone[76]

Oxycodone

Tapentadol

Oxymorphone[42,76] Tapentadol a

Although less affected by renal and hepatic impairment, methadone is generally not considered a first-line opioid in elderly patients.[8]

ª 2010 Adis Data Information BV. All rights reserved.

Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

423

4. Hepatic Impairment/Failure

and their metabolites. The prescribing information for most of the commonly prescribed opioids recommends caution in patients with hepatic impairment.[48-52,76] Generally, CYP-mediated metabolism is more affected by hepatic impairment, and glucuronidation is relatively spared,[82-84] but the effects of liver dysfunction on opioids metabolized solely by glucuronidation (e.g. morphine, hydromorphone, oxymorphone) are not insignificant. The clearance of morphine is reduced by ‡25% in hepatic failure, necessitating cautious dose adjustments.[84,85] Mean and maximum plasma concentrations of hydromorphone are each increased 4-fold in individuals with moderate hepatic impairment.[86] Oxymorphone is contraindicated in patients with moderate or severe hepatic dysfunction because clinical trials found its bioavailability increased 1.6- to 12.2-fold in such patients.[42] Data on tapentadol in patients with hepatic impairment are lacking. Conversely, the pharmacokinetics of fentanyl[87] and methadone[88] are not as substantially altered by hepatic impairment, even though these are CYP-metabolized drugs.[36] However, the effects of liver impairment on methadone are not entirely predictable. Patients with severe cirrhosis may actually require higher methadone doses because impairment of hepatic metabolism of methadone is offset by a loss of hepatic storage and release of methadone.[89] Although dosage adjustments may not be necessary in some patients with liver disease, practitioners should nonetheless be extremely cautious when prescribing any opioid for a patient with hepatic dysfunction. Table II presents recommendations for opioid prescribing in patients with hepatic impairment.

4.1 Who is at Risk?

Aging is accompanied by substantial decreases in both liver volume and hepatic blood flow.[77] This might be expected to reduce first-pass (e.g. CYP-mediated) drug metabolism, but as discussed in section 4.2, liver dysfunction does affect the metabolism of opioids that do not undergo extensive first-pass metabolism. Hepatic impairment should be suspected in patients with alcoholism, paracetamol overdose/ overuse, chronic hepatitis B or C, biliary tract obstruction, primary or secondary biliary cirrhosis, haemochromatosis and morbid obesity.[78] Clinical assessment of hepatic impairment is based on physical examination and laboratory tests. The Child-Pugh scale is a reliable assessment tool combining physical and laboratory findings that is recommended by the FDA as a measure of hepatic impairment in clinical trials.[79,80] In contrast to renal impairment, the relationship of clinically assessed hepatic impairment to alterations in drug pharmacokinetics is not straightforward. FDA-mandated hepatic dysfunction warnings in product labels may be based on clinical trials in which liver dysfunction was defined by quantitative liver function tests that are not typically available to clinicians.[80] These tests can reveal significant hepatic impairment when physical signs and standard laboratory tests remain within normal limits.[81] Consequently, if the product label for an opioid has a liver dysfunction warning, it may be prudent to prescribe the opioid with caution in patients who are at high risk of hepatic impairment (e.g. an alcoholic patient with hepatitis C or an obese patient who takes excessive amounts of paracetamol), even when physical examination and standard laboratory tests do not suggest hepatic impairment.

5. Cardio/Respiratory Impairment 5.1 Who is at Risk?

4.2 What are the Consequences for Opioid Selection?

Because opioids undergo biotransformation in the liver by CYP-mediated metabolism and/or by glucuronidation, hepatic impairment can cause accumulation and prolong the effect of opioids ª 2010 Adis Data Information BV. All rights reserved.

All opioids can cause respiratory depression, bradycardia and hypotension.[69,90-92] Pethidine is an exception, typically causing tachycardia via a vagolytic effect rather than bradycardia.[56] These effects may be of particular concern in patients who have impaired breathing or elevated Drugs Aging 2010; 27 (5)

Smith & Bruckenthal

424

cardiovascular risk independent of opioid use, including those with heart failure,[90,91] chronic obstructive pulmonary disease,[92] lung cancer[93] or sleep apnoea.[94,95] The risk of cardiovascular disease increases with age,[96] making the elderly more vulnerable to the potential cardiovascular effects of opioids. Research suggests that older patients are also much more likely than younger patients to experience respiratory depression during opioid therapy.[97] Respiratory problems are likely to exist in patients with a prolonged or heavy (>2 packs/day) smoking history. 5.2 What are the Consequences for Opioid Selection?

The majority of patients with elevated cardiovascular risk or respiratory disease can tolerate opioids, but these patients should be closely monitored for untoward effects. In elderly patients, opioids should be administered at a very low initial dose and titrated very gradually. Respiratory and cardiovascular function should be monitored throughout opioid therapy, but particularly early in treatment and after dose increases. Inpatients should be monitored for vital signs (cyanosis, lowered respiration rate, reduced heart rate, and hypotension), shortness of breath, rales and peripheral oedema. Hypotension typically precedes respiratory depression and is therefore a signal for impending cardiopulmonary distress. Outpatients and their families should be made aware of the signs of respiratory depression (fatigue, shortness of breath, cyanosis, somnolence, snoring), and heart failure (oedema, sudden weight gain). Appropriate clinical investigations may include oxygen saturation monitoring and/ or blood gas analyses, spirometry, ECG, chest radiographs, and possibly a sleep study if sleep apnoea is suspected. Some treatment centres will also monitor CO2 levels. Although all opioids can potentially affect cardiovascular function and suppress respiration, the degree to which different opioids exert these effects varies and will be influenced by the patient’s co-morbidities and concomitant medications, as well as opioid type, dose, interval, ª 2010 Adis Data Information BV. All rights reserved.

route and mechanisms of administration. To a large degree, this variation is based on the drug’s opioid-receptor binding profile.[98] For example, dextropropoxyphene is a weak analgesic because it is a weak m1-receptor agonist, but it is a potent bradycardic and respiratory depressant because it is a strong m2-receptor agonist.[57,98] Consequently, dextropropoxyphene has a reputation for causing dangerous degrees of cardiac and respiratory depression at doses that may fail to relieve pain, and it should not be used in patients with cardiovascular or respiratory complications.[57] The adverse cardiovascular effects of dextropropoxyphene are also attributable to the cardiotoxicity of its metabolite nordextropropoxyphene.[57,99] Like dextropropoxyphene, methadone has been associated with cardiotoxic effects (QT interval prolongation and several reports of fatal arrhythmias) and is challenging to use safely in the elderly.[100-102] Morphine is a strong agonist of both the m1- and m2-opioid receptors and is a safer choice than methadone or dextropropoxyphene for patients with cardiac and respiratory complications. However, use of morphine in patients with cardiac and respiratory risks must be undertaken with caution because it can cause respiratory depression and has been associated with dyspnoea, chest congestion, rales and a greater need for mechanical ventilation in patients with heart failure.[92] Codeine, although metabolized to morphine, is 10 times less potent than morphine as an analgesic and has been associated with profound hypotension and respiratory depression.[69,92] There may be exceptions to the presumptive associations that might be made between differences in the receptor binding profiles of individual opioids and their relative safety with respect to cardiac and respiratory effects. As a selective m1-receptor agonist, oxymorphone would be expected to provide a greater degree of analgesia than morphine relative to its effects on cardiac and respiratory function.[98,103] However, an early head-to-head comparison of oxymorphone with morphine found oxymorphone to be 8.95-fold more potent than morphine as an analgesic but 14.8-fold more potent than morphine as a respiratory depressant.[104] Consequently, oxymorphone Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

must be used just as cautiously as morphine in patients with cardiac and respiratory complications.[105] Oxycodone provides a significant portion of its analgesic effects via k-receptor agonism,[106] which is less likely to cause respiratory depression than agonism at the m-opioid receptor.[107,108] However, in head-to-head clinical trial comparisons with the m-receptor agonists morphine and tramadol, oxycodone produced a greater degree of respiratory depression.[108,109] Given the difficulty in predicting the risk of cardiovascular and respiratory effects with individual opioids, extreme caution should be used when administering any opioid to a patient with significant risk factors. Among long-acting opioids, methadone should be avoided and morphine, oxycodone and oxymorphone should be administered with caution. Tramadol has been recommended ahead of NSAIDs in patients with cardiovascular risk factors[110] and may be a safer option than codeine in patients for whom a weak opioid is indicated. 6. Cerebrovascular Disease, Dementia and Brain Injury 6.1 Who is at Risk?

Opioids are known to provoke or prolong delirium, hallucinations and cognitive impairment,[111-114] particularly in elderly patients with dementia, brain injury or other conditions that predispose to these events.[115] The relative propensity of different opioids for these adverse events is discussed in section 6.2, but in general, dose-dependent effects will be augmented by opioid dose, by pharmacokinetic effects reducing opioid metabolism or clearance, and by additive or synergistic pharmacodynamic drug interactions.[36] Euphoric, dysphoric and adverse cognitive effects of opioids are also heightened by rapid onset of action, which can be influenced by the route of administration (e.g. oral vs intravenous)[116] and by characteristics of the opioid molecule and formulation.[117] Opioids also pose a general risk in patients with head injury or increased intracranial presª 2010 Adis Data Information BV. All rights reserved.

425

sure, because of the possibility of reduced blood pressure, increased respiratory depression and elevated cerebrospinal fluid pressure.[118,119] 6.2 What are the Consequences for Opioid Selection?

Cognitive impairment, delirium and hallucinations can occur with any opioid but are most common with pethidine.[111,116] Delirium is a frequent adverse event with morphine,[112,113] and both delirium and cognitive decline have been reported with hydromorphone.[115,120] These effects are thought to be related to neurotoxicity of active metabolites that accumulate during treatment.[114] Specifically, the neurocognitive effects of pethidine have been attributed to the anticholinergic activity of its norpethidine metabolite.[114] Morphine-associated delirium is believed to stem from the neuroexcitatory effects of its morphine-3-glucuronide metabolite,[114] as described in section 3.2. Like morphine, hydromorphone has active metabolites with neuroexcitatory effects that can produce delirium.[115,120] Clinicians may therefore consider avoiding pethidine, morphine and hydromorphone in patients with dementia or cerebrovascular disease, but should also carefully monitor for dysphoria, delirium and adverse cognitive effects with any older patient prescribed an opioid. Reports of increased intracranial pressure have primarily involved fentanyl, sufentanil and alfentanil.[118,119] These agents should be avoided in patients with head trauma. Blood pressure should be monitored closely in patients with head trauma receiving opioids, because hypotension can indicate raised intracranial pressure, which may swiftly lead to respiratory depression and cardiopulmonary distress.[119] 7. Limited Routes of Administration 7.1 Who is at Risk?

Although the oral route for opioid administration is preferred by most patients requiring opioid analgesia,[22] patients with cancer of the head and neck, neurological disorders, or gastrooesophageal reflux disease and other swallowing Drugs Aging 2010; 27 (5)

Smith & Bruckenthal

426

problems may have difficulties with some orally administered medications. Oral administration is also problematic for patients with severe nausea and vomiting,[121] including cancer patients undergoing radiation or chemotherapy, patients with gastrointestinal obstruction, and patients with cognitive or psychiatric disorders, who may be noncompliant because they are unwilling to take medications orally. Both international[122] and US[8] guidelines for the use of opioids in elderly patients acknowledge that alternative delivery routes may be necessary in patients with swallowing difficulties or who are otherwise noncompliant with oral treatment. 7.2 What are the Consequences for Opioid Selection?

It may be helpful to consider less frequent oral dosing with a long-acting opioid, such as: (i) once-daily morphine; (ii) a once- or twice-daily morphine/naltrexone combination; or (iii) twicedaily morphine ER (generic), oxycodone controlled release (CR) [generic], oxymorphone ER or tramadol ER. An ER formulation of tapentadol should also soon be available in the US. Rectal delivery as an alternative to oral administration is available with many opioids, including morphine, hydromorphone and oxycodone, but may require dose adjustment. Transdermal delivery is available with fentanyl (generic), and transdermal buprenorphine is approved in Europe and will likely come to the US soon. Fentanyl is inefficient when taken orally because so much of it is destroyed by first-pass metabolism (low oral bioavailability). Transmucosal fentanyl (fentanyl buccal tablets, oral fentanyl citrate and fentanyl buccal soluble film) has a narrow indication for breakthrough cancer pain in patients already receiving and able to tolerate opioid therapy.[123] Intranasal butorphanol (generic) is prescribed infrequently for pain indications other than migraine owing to its much-publicized abuse potential.[124] When patients are not amenable to rectal, transdermal or transmucosal opioid administration, more invasive methods of administration – such as intravenous, intramuscular, intrathecal or epidural injection – may be necessary. Fentaª 2010 Adis Data Information BV. All rights reserved.

nyl, hydromorphone, morphine, oxymorphone and buprenorphine are available in formulations for injection. Morphine has been formulated for epidural or intrathecal injection. Intrathecal morphine has been associated infrequently with granuloma formation at higher doses, resulting in spinal cord compression.[125,126] Alternatively, an epidural formulation of morphine has been developed to provide 48 hours of continuous analgesia with a single injection.[127] Intrathecal use of fentanyl or hydromorphone has also been recommended owing to their relative granuloma-sparing effects.[125,128] Ultimately, opioid selection in patients for whom oral administration is problematic should take into account factors such as pharmacokinetics (e.g. time to maximum effect, duration of effect, metabolism and clearance) and cost, which also differ based on route of administration. When nausea and vomiting are concerns, prescribers should remember that changing the route of administration may not reduce gastrointestinal adverse events, because direct effects of opioids in the gastrointestinal tract account for only some of these events. Opioid-mediated stimulation of brain centres that trigger nausea and vomiting also upset the stomach, which explains why patients frequently experience gastrointestinal adverse events while taking intravenous or transdermal opioids.[121] For such patients, prescribers may consider administering a selective serotonin 5-HT3-receptor antagonist, which acts centrally, to inhibit the vomit reflex in the brain.[129] Ultimately, if gastrointestinal adverse effects are intolerable and cannot be managed, it may be necessary to switch opioids rather than switch the route of administration. Advantages and disadvantages of each delivery route are listed in table III. 8. Psychiatric Illness and Addiction 8.1 Who is at Risk?

Mental illness and personality disorders, including bipolar affective disorder, major depressive disorder, dysthymia, panic disorder, generalized anxiety disorder, borderline personality disorder Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

427

Table III. Available routes of administration of common opioid analgesics and suitability for the patient with medical complications Route of administration

Opioid

Potentially problematic medical complications

Epidural or intrathecal

Morphine

Anticoagulant therapy, haemostatic disorder, psychiatric disorder, risk of infection

Oral

Codeine, hydromorphone, methadone, morphine CR, morphine ER, oxycodone CR, oxycodone IR, oxymorphone IR, oxymorphone ER, tapentadol, tramadol ER

Dysphagia, gastrointestinal obstruction, nausea and vomiting, non-compliance, abuse, diversion

Intramuscular or subcutaneous

Hydromorphone, morphine

Skin irritation

Intravenous

Buprenorphine, fentanyl, hydromorphone, morphine, oxymorphone

Limited venous access, risk of infection (immunocompromised patients), skin irritation, weakened veins (chemotherapy patients)

Rectal

Hydromorphone, morphine, oxycodone

Anal fissures, constipation, haemorrhoids, patient resistance

Transdermal

Fentanyl

Skin irritation, cognitive or psychiatric disorders

Transmucosal

Fentanyl

Nausea and vomiting, non-compliance, oral pain, poor oral health (lozenge), abuse/misuse

CR = controlled release; ER = extended release; IR = immediate release.

and polysubstance abuse, are more common among patients using opioid analgesia.[27] Psychiatric patients are also generally more at risk for substance abuse,[130] with up to 60% of patients with bipolar disorder abusing substances at some time in their lives[131] and certain personality disorders being associated with a 6- to 12-fold risk of developing substance abuse.[132] In patients prescribed opioids, epidemiological data suggest that mental health disorders (particularly borderline personality disorder and polysubstance abuse) are a significant predictor of opioid abuse, diversion and dependence among patients using opioids for chronic noncancer pain.[133] Substance abuse and addiction in the elderly are not considered major concerns by most prescribers. In 2007, a national survey by the US Department of Health and Human Services found that the prevalence of drug abuse by Americans aged ‡65 years (0.7%) was about 10-fold lower than that of the population aged ‡12 years (8%).[134] However, a history of substance abuse is a significant predictor of substance abuse regardless of patient age,[135] and geriatric pain specialists recommend including abuse-risk screening questions in the assessment of elderly patients considering opioid therapy.[136] Moreover, when older patients are diagnosed with addiction, their drug source is predominantly found ª 2010 Adis Data Information BV. All rights reserved.

to be prescribed medications.[137] Another important consideration is that elderly patients with mental health problems such as depression and anxiety may be unnecessarily prescribed drugs with potential for abuse and addiction when prescribers fail to recognize somatization of mental health complaints.[29] 8.2 What are the Consequences for Opioid Selection?

When prescribing opioid analgesics to patients with psychiatric disorders, it is essential that physicians know the relative risk for psychiatric adverse events of concurrent psychiatric medications. Because all opioids have the potential for DDIs and additive depressant effects with other CNS depressants, dose modification and monitoring are necessary in patients taking medications such as antidepressants, sedatives and phenothiazines (see section 2; table I). Consultation with the patient’s prescribing mental health professional or the primary care physician prescribing the psychiatric medications is advisable. When drug abuse is a particular concern, reference to US Drug Enforcement Administration (DEA) classifications for addiction potential is of limited use for guiding prescribing.[138] The DEA lists morphine, codeine, fentanyl, hydrocodone, Drugs Aging 2010; 27 (5)

Smith & Bruckenthal

428

hydromorphone, methadone, oxycodone, oxymorphone, other pure opioids and the partial m-receptor agonist tapentadol as having high addiction potential (schedule II status). Combination products containing codeine, hydrocodone or morphine are listed as having moderate addiction potential (schedule III status). The lone exceptions are oxycodone combination products (e.g. oxycodone/paracetamol, oxycodone/acetylsalicylic acid), which have schedule II status based on their potential for abuse.[138] Practitioners should bear in mind that combination products may not be indicated for severe pain[139] and that most include paracetamol, which is hepatotoxic at doses >4 g/day. The paracetamol component imposes a dosage ceiling on combination products, making them of limited value in patients requiring long-term opioid therapy with periodic dose escalation. Buprenorphine, a partial m-receptor agonist, is a schedule III drug that is frequently used in patients requiring detoxification for opioid addiction.[140] This opioid may be an option in patients with a history of abuse who nonetheless require therapy to manage chronic pain.[7] Tramadol is the only nonscheduled opioid-like analgesic[138] and appears to have less abuse potential.[141,142] However, as stated above, tramadol is a partial m-receptor agonist, exerting most of its analgesic effects via other mechanisms. Studies conducted in the US as recently as 2006 indicate that oxycodone CR and hydrocodone are the most frequently abused opioid analgesics.[139,143,144] In any patient prescribed opioids, and particularly those with psychiatric co-morbidities or elevated risk of abuse, vigilant monitoring for signs of abuse is highly recommended.[145,146] It is always important to take a thorough history when considering opioids for the elderly patient, not only to assess risks posed by medical conditions and concurrent medications, but to screen for mental health and substance abuse history. Although substance abuse is less prevalent in older patients, it is advisable to adopt a universal precautions approach to monitoring opioid-treated patients.[145,147] Urine drug testing can be accomplished using a combination of ª 2010 Adis Data Information BV. All rights reserved.

point-of-care immunoassays for predetermined panels of target drugs and confirmatory laboratory tests in the event of positive immunoassay findings.[147] The support of an experienced laboratory for proper test selection and interpretation is a valuable therapeutic asset. Cone and Caplan[147] published a practical review of urine drug monitoring for opioid prescribers in 2009.

9. Conclusion Opioids remain essential in the treatment of postoperative pain and cancer pain and are gaining acceptance for the treatment of chronic noncancer pain.[7] Many patients receiving opioid analgesic therapy have medical complications, and these are important considerations for prescribing. There are differences in the relative appropriateness of various opioid analgesics for medically complicated patients due to the effects that disease states and their treatments have on opioid metabolism and elimination, the likelihood of DDIs, the routes of administration, and the risk of amplifying the adverse effects of opioids in general or some opioids in particular. Applying clinical skills to identify the medically complicated patient and pharmaceutical knowledge to select the most appropriate opioid can ensure safe and effective prescribing. Acknowledgements Jeffrey Coleman and Nicole Strangman of Complete Healthcare Communications Inc., Chadds Ford, PA, USA, provided editorial support (literature search, document retrieval, writing and proofing) for this manuscript with funding provided by Endo Pharmaceuticals Inc., Chadds Ford, PA, USA. Endo Pharmaceuticals made no contribution to the content of this manuscript. However, a courtesy copy of the finished manuscript was forwarded to Endo Pharmaceuticals at the time of submission. Dr Smith has no affiliations or financial involvement with any organization or entity with a financial interest in the subject matter discussed in the manuscript. Dr Bruckenthal has received unrestricted educational grants from Endo Pharmaceuticals (Chadds Ford, PA, USA), Cephalon Inc. (Frazer, PA, USA) and Ameritox Ltd (Baltimore, MD, USA). Neither author has received any direct or indirect commercial financial incentive associated with publishing this article.

Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

References 1. American Society of Anesthesiologists. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2004 Jun; 100 (6): 1573-81 2. American Society of Anesthesiologists. Practice guidelines for cancer pain management: a report by the American Society of Anesthesiologists Task Force on Pain Management, Cancer Pain Section. Anesthesiology 1996; 84: 1243-57 3. Benedetti C, Brock C, Cleeland C, et al. NCCN practice guidelines for cancer pain. Oncology (Huntingt) 2000 Nov; 14 (11A): 135-50 4. American Society of Anesthesiologists. Practice guidelines for chronic pain management: a report by the American Society of Anesthesiologists Task Force on Pain Management, Chronic Pain Section. Anesthesiology 1997; 86: 995-1004 5. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med 2007 Oct 2; 147 (7): 478-91 6. American Pain Society. Guideline for the management of pain in osteoarthritis, rheumatoid arthritis and juvenile chronic arthritis. Chicago (IL): American Pain Society, 2002 7. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009 Feb; 10 (2): 113-30 8. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009 Aug; 57 (8): 1331-46 9. National Collaborating Centre for Chronic Conditions. Osteoarthritis: the care and management of osteoarthritis in adults. London, UK: Royal College of Physicians, 2008 10. Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16 (2): 137-62 11. Portenoy RK. Opioid therapy for chronic nonmalignant pain: a review of the critical issues. J Pain Symptom Manage 1996 Apr; 11 (4): 203-17 12. Hudson TJ, Edlund MJ, Steffick DE, et al. Epidemiology of regular prescribed opioid use: results from a national, population-based survey. J Pain Symptom Manage 2008 Sep; 36 (3): 280-8 13. Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain 2004 Dec; 112 (3): 372-80 14. Trescot AM, Helm S, Hensen H, et al. Opioids in the management of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’ (ASIPP) Guidelines. Pain Physician 2008; 11: S5-62 15. Chamberlin KW, Cottle M, Neville R, et al. Oral oxymorphone for pain management. Ann Pharmacother 2007 Jul; 41 (7): 1144-52

ª 2010 Adis Data Information BV. All rights reserved.

429

16. Smith HS. Drugs for pain. Philadelphia (PA): Hanley & Belfus, Inc., 2003 17. Tzschentke TM, Christoph T, Kogel B, et al. (-)-(1R,2R)-3(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broadspectrum analgesic properties. J Pharmacol Exp Ther 2007 Oct; 323 (1): 265-76 18. Fick DM, Cooper JW, Wade WE, et al. Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med 2003 Dec 8-22; 163 (22): 2716-24 19. Riley J, Ross JR, Rutter D, et al. No pain relief from morphine? Individual variation in sensitivity to morphine and the need to switch to an alternative opioid in cancer patients. Support Care Cancer 2006 Jan; 14 (1): 56-64 20. Galer BS, Coyle N, Pasternak GW, et al. Individual variability in the response to different opioids: report of five cases. Pain 1992 Apr; 49 (1): 87-91 21. Berndt S, Maier C, Schutz HW. Polymedication and medication compliance in patients with chronic nonmalignant pain. Pain 1993 Mar; 52 (3): 331-9 22. Parsells Kelly J, Cook SF, Kaufman DW, et al. Prevalence and characteristics of opioid use in the US adult population. Pain 2008 Sep 15; 138 (3): 507-13 23. Hajjar ER, Cafiero AC, Hanlon JT. Polypharmacy in elderly patients. Am J Geriatr Pharmacother 2007 Dec; 5 (4): 345-51 24. Preskorn SH, Silkey B, Shah R, et al. Complexity of medication use in the Veterans Affairs healthcare system, part I: outpatient use in relation to age and number of prescribers. J Psychiatr Pract 2005 Jan; 11 (1): 5-15 25. Tulner LR, Frankfort SV, Gijsen GJ, et al. Drug-drug interactions in a geriatric outpatient cohort: prevalence and relevance. Drugs Aging 2008; 25 (4): 343-55 26. Malhotra S, Karan RS, Pandhi P, et al. Drug related medical emergencies in the elderly: role of adverse drug reactions and non-compliance. Postgrad Med J 2001 Nov; 77 (913): 703-7 27. Sullivan MD, Edlund MJ, Steffick D, et al. Regular use of prescribed opioids: association with common psychiatric disorders. Pain 2005 Dec 15; 119 (1-3): 95-103 28. Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry 2005 Sep; 187: 243-7 29. Barkin RL, Barkin SJ. Reexamining the elderly patient’s presentation with depression. Prim Care Companion J Clin Psychiatry 2008; 10 (5): 415-6 30. Sokol KC, Knudsen JF, Li MM. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther 2007 Apr; 32 (2): 169-75 31. Yassen A, Olofsen E, van Dorp E, et al. Mechanism-based pharmacokinetic-pharmacodynamic modelling of the reversal of buprenorphine-induced respiratory depression by naloxone: a study in healthy volunteers. Clin Pharmacokinet 2007; 46 (11): 965-80 32. Hendrickx JF, Eger 2nd EI, Sonner JM, et al. Is synergy the rule? A review of anesthetic interactions producing hypnosis and immobility. Anesth Analg 2008 Aug; 107 (2): 494-506

Drugs Aging 2010; 27 (5)

430

33. Ailawadhi S, Sung KW, Carlson LA, et al. Serotonin syndrome caused by interaction between citalopram and fentanyl. J Clin Pharm Ther 2007 Apr; 32 (2): 199-202 34. Zhou SF, Xue CC, Yu XQ, et al. Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit 2007 Dec; 29 (6): 687-710 35. Flockhart DA. Drug interactions: cytochrome P450 drug interaction table [online]. Available from URL: http:// medicine.iupui.edu/flockhart/table.htm [Accessed 2009 Oct 29] 36. Smith HS. Opioid metabolism. Mayo Clin Proc 2009 Jul; 84 (7): 613-24 37. Foster A, Mobley E, Wang Z. Complicated pain management in a CYP450 2D6 poor metabolizer. Pain Pract 2007 Dec; 7 (4): 352-6 38. Susce MT, Murray-Carmichael E, de Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry 2006 Sep 30; 30 (7): 1356-8 39. Heiskanen T, Kalso E, Olkkola KT. Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 1998 Dec; 64 (6): 603-11 40. Coffman BL, Rios GR, King CD, et al. Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos 1997 Jan; 25 (1): 1-4 41. Dilaudid Oral Liquid and Dilaudid Tablets (hydromorphone hydrochloride): US prescribing information. Stamford (CT): Purdue Pharma, LLP, 2008 42. OPANA ER (oxymorphone hydrochloride extended-release tablets): US prescribing information. Chadds Ford (PA): Endo Pharmaceuticals Inc., 2008 43. Adams M, Pieniaszek Jr HJ, Gammaitoni AR, et al. Oxymorphone extended release does not affect CYP2C9 or CYP3A4 metabolic pathways. J Clin Pharmacol 2005 Mar; 45 (3): 337-45 44. Kneip C, Terlinden R, Beier H, et al. Investigations into the drug-drug interaction potential of tapentadol in human liver microsomes and fresh human hepatocytes. Drug Metab Lett 2008 Jan; 2 (1): 67-75 45. de Wildt SN, Kearns GL, Leeder JS, et al. Glucuronidation in humans: pharmacogenetic and developmental aspects. Clin Pharmacokinet 1999 Jun; 36 (6): 439-52 46. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 1985 Apr; 33 (4): 278-85 47. Rowe JW, Andres R, Tobin JD, et al. The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J Gerontol 1976 Mar; 31 (2): 155-63 48. Codeine Contin (codeine controlled release tablets): US prescribing information. Pickering (ON): Purdue Pharma, LLP, 1994 49. Kadian (morphine sulfate sustained release capsules): US prescribing information. Piscataway (NJ): Alpharma, 2007 50. OxyContin (oxycodone HCl controlled-release tablets): US prescribing information. Stamford (CT): Purdue Pharma LLP, 2007

ª 2010 Adis Data Information BV. All rights reserved.

Smith & Bruckenthal

51. Duragesic (fentanyl transdermal system): US prescribing information. Titusville (NJ): Janssen Pharmaceuticals, Inc., 2008 52. Hydromorphone-HP Injection 10 mg (hydromorphone hydrochloride): US prescribing information. North Chicago (IL): Abbott Laboratories, 2008 53. McMillan JI. Renal failure. In: Porter RS, editor. The Merck manual online. 18th ed. Whitehouse Station (NJ): Merck Research Laboratories, 2007 54. Guidance for industry: pharmacokinetics in patients with impaired renal function – study design, data analysis, and impact on dosing and labeling. Rockville (MD): US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER), 1998 55. Hassan H, Bastani B, Gellens M. Successful treatment of normeperidine neurotoxicity by hemodialysis. Am J Kidney Dis 2000 Jan; 35 (1): 146-9 56. Jiraki K. Lethal effects of normeperidine. Am J Forensic Med Pathol 1992 Mar; 13 (1): 42-3 57. Barkin RL, Barkin SJ, Barkin DS. Propoxyphene (dextropropoxyphene): a critical review of a weak opioid analgesic that should remain in antiquity. Am J Ther 2006 Nov-Dec; 13 (6): 534-42 58. Milne RW, Nation RL, Somogyi AA, et al. The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive-care patients. Br J Clin Pharmacol 1992 Jul; 34 (1): 53-9 59. Pauli-Magnus C, Hofmann U, Mikus G, et al. Pharmacokinetics of morphine and its glucuronides following intravenous administration of morphine in patients undergoing continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 1999 Apr; 14 (4): 903-9 60. Wolff J, Bigler D, Christensen CB, et al. Influence of renal function on the elimination of morphine and morphine glucuronides. Eur J Clin Pharmacol 1988; 34 (4): 353-7 61. Sear JW, Hand CW, Moore RA, et al. Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites. Br J Anaesth 1989 Jan; 62 (1): 28-32 62. Chauvin M, Sandouk P, Scherrmann JM, et al. Morphine pharmacokinetics in renal failure. Anesthesiology 1987 Mar; 66 (3): 327-31 63. Angst MS, Buhrer M, Lotsch J. Insidious intoxication after morphine treatment in renal failure: delayed onset of morphine-6-glucuronide action. Anesthesiology 2000 May; 92 (5): 1473-6 64. Dubs A, Wiedemeier P, Caduff B. Morphine poisoning in chronic kidney failure: morphine-6-glucuronide as a pharmacologically active morphine metabolite. Dtsch Med Wochenschr 1999 Jul 30; 124 (30): 896-8 65. Hagen NA, Foley KM, Cerbone DJ, et al. Chronic nausea and morphine-6-glucuronide. J Pain Symptom Manage 1991 Apr; 6 (3): 125-8 66. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000 Jul; 27 (7): 524-8

Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

67. Babul N, Darke AC, Hagen N. Hydromorphone metabolite accumulation in renal failure. J Pain Symptom Manage 1995 Apr; 10 (3): 184-6 68. Guay DR, Awni WM, Findlay JW, et al. Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease. Clin Pharmacol Ther 1988 Jan; 43 (1): 63-71 69. Talbott GA, Lynn AM, Levy FH, et al. Respiratory arrest precipitated by codeine in a child with chronic renal failure. Clin Pediatr (Phila) 1997 Mar; 36 (3): 171-3 70. Barkin RL. Extended-release tramadol (ULTRAM ER): a pharmacotherapeutic, pharmacokinetic, and pharmacodynamic focus on effectiveness and safety in patients with chronic/persistent pain. Am J Ther 2008 Mar-Apr; 15 (2): 157-66 71. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004 Nov; 28 (5): 497-504 72. Murtagh FE, Chai MO, Donohoe P, et al. The use of opioid analgesia in end-stage renal disease patients managed without dialysis: recommendations for practice. J Pain Palliat Care Pharmacother 2007; 21 (2): 5-16 73. Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999 Jul; 37 (1): 17-40 74. Davis M. Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics. Clin Pharmacokinet 2007; 46 (10): 825-50 75. Lugo RA, Kern SE. The pharmacokinetics of oxycodone. J Pain Palliat Care Pharmacother 2004; 18 (4): 17-30 76. Vicodin (hydrocodone bitartrate and acetaminophen): US prescribing information. Corona (CA): Watson Pharma, 2006 77. Wynne HA, Cope LH, Mutch E, et al. The effect of age upon liver volume and apparent liver blood flow in healthy man. Hepatology 1989 Feb; 9 (2): 297-301 78. Heidelbaugh JJ, Bruderly M. Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician 2006 Sep 1; 74 (5): 756-62 79. Riley 3rd TR, Bhatti AM. Preventive strategies in chronic liver disease, part II: cirrhosis. Am Fam Physician 2001 Nov 15; 64 (10): 1735-40 80. Guidance for industry: pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Rockville (MD): US Department of Health and Human Services; Food and Drug Administration; Center for Drug Evaluation and Research (CDER); Center for Biologics Evaluation and Research (CBER), 2003 81. Everson GT, Shiffman ML, Morgan TR, et al. The spectrum of hepatic functional impairment in compensated chronic hepatitis C: results from the Hepatitis C Anti-viral Long-term Treatment against Cirrhosis Trial. Aliment Pharmacol Ther 2008 May; 27 (9): 798-809 82. Furlan V, Demirdjian S, Bourdon O, et al. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 1999 May; 289 (2): 1169-75 83. Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol 2003 Feb; 9 (2): 359-63

ª 2010 Adis Data Information BV. All rights reserved.

431

84. Crotty B, Watson KJ, Desmond PV, et al. Hepatic extraction of morphine is impaired in cirrhosis. Eur J Clin Pharmacol 1989; 36 (5): 501-6 85. Hasselstrom J, Eriksson S, Persson A, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990 Mar; 29 (3): 289-97 86. Durnin C, Hind ID, Ghani SP, et al. Pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR) in subjects with moderate hepatic impairment. Proc West Pharmacol Soc 2001; 44: 83-4 87. Haberer JP, Schoeffler P, Couderc E, et al. Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis. Br J Anaesth 1982 Dec; 54 (12): 1267-70 88. Novick DM, Kreek MJ, Fanizza AM, et al. Methadone disposition in patients with chronic liver disease. Clin Pharmacol Ther 1981 Sep; 30 (3): 353-62 89. Smith HS, Kreek MJ, Johnson CL. Pain and chemical dependency. New York (NY): Oxford University Press, 2008 90. Cattermole GN, Graham CA. Opiates should be avoided in acute decompensated heart failure. Emerg Med J 2009 Mar; 26 (3): 230-1 91. Peacock WF, Hollander JE, Diercks DB, et al. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis. Emerg Med J 2008 Apr; 25 (4): 205-9 92. Gruber EM, Tschernko EM. Anaesthesia and postoperative analgesia in older patients with chronic obstructive pulmonary disease: special considerations. Drugs Aging 2003; 20 (5): 347-60 93. Kvale PA, Selecky PA, Prakash UB. Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007 Sep; 132 (3 Suppl.): 368S-403S 94. Webster LR, Choi Y, Desai H, et al. Sleep-disordered breathing and chronic opioid therapy. Pain Med 2008 May-Jun; 9 (4): 425-32 95. Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007 Aug 15; 3 (5): 455-61 96. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007 Feb 6; 115 (5): e69-171 97. Cepeda MS, Farrar JT, Baumgarten M, et al. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther 2003 Aug; 74 (2): 102-12 98. Barkin RL, Iusco AM, Barkin SJ. Opioids used in primary care for the management of pain: a pharmacologic, pharmacotherapeutic, and pharmacodynamic overview. In: Boswell MV, Cole BE, editors. Weiner’s pain management: a practical guide for clinicians. 7th ed. New York (NY): CRC Press/Taylor & Francis Group, 2006 99. Ulens C, Daenens P, Tytgat J. Norpropoxyphene-induced cardiotoxicity is associated with changes in ion-selectivity and gating of HERG currents. Cardiovasc Res 1999 Dec; 44 (3): 568-78

Drugs Aging 2010; 27 (5)

432

100. Fanoe S, Hvidt C, Ege P, et al. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007; 93: 1051-5 101. Wedam EF, Bigelow GE, Johnson RE, et al. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial. Arch Intern Med 2007 Dec 10; 167 (22): 2469-75 102. Gallagher R. Methadone: an effective, safe drug of first choice for pain management in frail older adults. Pain Med 2009 Mar; 10 (2): 319-26 103. Venkatesan P, Baxi S, Evans C, et al. Glycinergic inputs to cardiac vagal neurons in the nucleus ambiguus are inhibited by nociceptin and mu-selective opioids. J Neurophysiol 2003 Sep; 90 (3): 1581-8 104. Bellville JW, Escarraga LA, Wallenstein SL, et al. Relative respiratory depressant effects of oxymorphone (Numorphan) and morphine. Anesthesiology 1960 Jul-Aug; 21: 397-400 105. Sloan PA, Barkin RL. Oxymorphone and oxymorphone extended release: a pharmacotherapeutic review. J Opioid Manag 2008 May-Jun; 4 (3): 131-44 106. Nielsen CK, Ross FB, Lotfipour S, et al. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain 2007 Dec 5; 132 (3): 289-300 107. Dahan A. Respiratory depression with opioids. J Pain Palliat Care Pharmacother 2007; 21 (1): 63-6 108. Dahan A, Sarton E, Teppema L, et al. Anesthetic potency and influence of morphine and sevoflurane on respiration in mu-opioid receptor knockout mice. Anesthesiology 2001 May; 94 (5): 824-32 109. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and oxycodone. J Clin Anesth 1997 Nov; 9 (7): 582-5 110. Antman EM, Bennett JS, Daugherty A, et al. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007 Mar 27; 115 (12): 1634-42 111. Morrison RS, Magaziner J, Gilbert M, et al. Relationship between pain and opioid analgesics on the development of delirium following hip fracture. J Gerontol A Biol Sci Med Sci 2003 Jan; 58 (1): 76-81 112. Morita T, Takigawa C, Onishi H, et al. Opioid rotation from morphine to fentanyl in delirious cancer patients: an open-label trial. J Pain Symptom Manage 2005 Jul; 30 (1): 96-103 113. Morita T, Tei Y, Tsunoda J, et al. Increased plasma morphine metabolites in terminally ill cancer patients with delirium: an intra-individual comparison. J Pain Symptom Manage 2002 Feb; 23 (2): 107-13 114. Lawlor PG. The panorama of opioid-related cognitive dysfunction in patients with cancer: a critical literature appraisal. Cancer 2002 Mar 15; 94 (6): 1836-53 115. Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients: a systematic review. Anesth Analg 2006 Apr; 102 (4): 1255-66 116. Ersek M, Cherrier MM, Overman SS, et al. The cognitive effects of opioids. Pain Manag Nurs 2004 Jun; 5 (2): 75-93

ª 2010 Adis Data Information BV. All rights reserved.

Smith & Bruckenthal

117. Webster LR, Bath B, Medve RA. Opioid formulations in development designed to curtail abuse: who is the target? Expert Opin Investig Drugs 2009 Mar; 18 (3): 255-63 118. Albanese J, Viviand X, Potie F, et al. Sufentanil, fentanyl, and alfentanil in head trauma patients: a study on cerebral hemodynamics. Crit Care Med 1999 Feb; 27 (2): 407-11 119. Jamali S, Ravussin P, Archer D, et al. The effects of bolus administration of opioids on cerebrospinal fluid pressure in patients with supratentorial lesions. Anesth Analg 1996 Mar; 82 (3): 600-6 120. Leung JM, Sands LP, Paul S, et al. Does postoperative delirium limit the use of patient-controlled analgesia in older surgical patients? Anesthesiology 2009 Sep; 111 (3): 625-31 121. Porreca F, Ossipov MH. Nausea and vomiting side effects with opioid analgesics during treatment of chronic pain: mechanisms, implications, and management options. Pain Med 2009 May-Jun; 10 (4): 654-62 122. Pergolizzi J, Boger RH, Budd K, et al. Opioids and the management of chronic severe pain in the elderly: consensus statement of an international expert panel with focus on the six clinically most often used World Health Organization step III opioids (buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract 2008 Jul-Aug; 8 (4): 287-313 123. Fentora (fentanyl buccal tablet): US prescribing information. Frazer (PA): Cephalon, 2007 124. Loder E. Post-marketing experience with an opioid nasal spray for migraine: lessons for the future. Cephalalgia 2006 Feb; 26 (2): 89-97 125. Smith HS, Deer TR, Staats PS, et al. Intrathecal drug delivery. Pain Physician 2008 Mar; 11 (2 Suppl.): S89-104 126. Peng P, Massicotte EM. Spinal cord compression from intrathecal catheter-tip inflammatory mass: case report and a review of etiology. Reg Anesth Pain Med 2004 May-Jun; 29 (3): 237-42 127. Viscusi ER, Martin G, Hartrick CT, et al. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology 2005 May; 102 (5): 1014-22 128. Deer TR, Krames ES, Hassenbusch SJ, et al. Polyanalgesic Consensus Conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery – report of an interdisciplinary expert panel. Neuromodulation 2007 October; 10 (4): 300-28 129. Zofran (ondansetron): US prescribing information. Research Triangle Park (NC): GlaxoSmithKline, 2004 130. Compton 3rd WM, Cottler LB, Jacobs JL, et al. The role of psychiatric disorders in predicting drug dependence treatment outcomes. Am J Psychiatry 2003 May; 160 (5): 890-5 131. Krishnan KR. Psychiatric and medical comorbidities of bipolar disorder. Psychosom Med 2005 Jan-Feb; 67 (1): 1-8 132. Cohen P, Chen H, Crawford TN, et al. Personality disorders in early adolescence and the development of later substance use disorders in the general population. Drug Alcohol Depend 2007 Apr; 88 (Suppl. 1): S71-84 133. Edlund MJ, Steffick D, Hudson T, et al. Risk factors for clinically recognized opioid abuse and dependence among

Drugs Aging 2010; 27 (5)

Opioids for Medically Complicated Patients

134.

135.

136.

137.

138.

139.

140.

veterans using opioids for chronic non-cancer pain. Pain 2007 Jun; 129 (3): 355-62 US Department of Health and Human Services Substance Abuse and Mental Health Services Administration. 2007 national survey of drug use & health: table 1.1A [online]. Available from URL: http://www.oas.samhsa.gov/ NSDUH/2k7NSDUH/tabs/Sect1peTabs1to46.htm [Accessed 2010 Apr 14] Manchikanti L, Cash KA, Damron KS, et al. Controlled substance abuse and illicit drug use in chronic pain patients: an evaluation of multiple variables. Pain Physician 2006 Jul; 9 (3): 215-25 Kirsh KL, Smith HS. Special issues and concerns in the evaluation of older adults who have pain. Clin Geriatr Med 2008 May; 24 (2): 263-74, vi Sproule B, Brands B, Li S, et al. Changing patterns in opioid addiction: characterizing users of oxycodone and other opioids. Can Fam Physician 2009 Jan; 55 (1): 68-9, 9 e1-5 US Department of Justice Drug Enforcement Administration. Controlled substances in alphabetical order [online]. Available from URL: http://www.deadiversion.usdoj. gov/schedules/orangebook/c_cs_alpha.pdf [Accessed 2009 Oct 29] Joranson DE, Ryan KM, Gilson AM, et al. Trends in medical use and abuse of opioid analgesics. JAMA 2000 Apr 5; 283 (13): 1710-4 Meader N. A comparison of methadone, buprenorphine and alpha(2) adrenergic agonists for opioid detoxifica-

ª 2010 Adis Data Information BV. All rights reserved.

433

141.

142.

143.

144.

145.

146. 147.

tion: a mixed treatment comparison meta-analysis. Drug Alcohol Depend 2010 Apr; 108 (1-2): 110-4 Raffa RB. Basic pharmacology relevant to drug abuse assessment: tramadol as example. J Clin Pharm Ther 2008 Apr; 33 (2): 101-8 Adams EH, Breiner S, Cicero TJ, et al. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage 2006 May; 31 (5): 465-76 Cicero TJ, Inciardi JA, Munoz A. Trends in abuse of oxycontin and other opioid analgesics in the United States: 2002-2004. J Pain 2005 Oct; 6 (10): 662-72 Katz N, Fernandez K, Chang A, et al. Internet-based survey of nonmedical prescription opioid use in the United States. Clin J Pain 2008 Jul-Aug; 24 (6): 528-35 Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med 2005 Mar-Apr; 6 (2): 107-12 Heit HA, Gourlay DL. Urine drug testing in pain medicine. J Pain Symptom Manage 2004 Mar; 27 (3): 260-7 Cone EJ, Caplan YH. Urine toxicology testing in chronic pain management. Postgrad Med 2009 Jul; 121 (4): 91-102

Correspondence: Dr Howard Smith, Department of Anesthesiology, Albany Medical College, 47 New Scotland Avenue, MC-131, Albany, NY 12208, USA. E-mail: [email protected]

Drugs Aging 2010; 27 (5)