The use of naturally occurring plant material for the relief of pain dates back to early times. Advances in antipyretic and analgesic medications began in the late 1800s with the development of salicylic acid, antipyrine, phenacetin, and acetaminophen (APAP). These basic medications are still used today to various degrees in both over-the-counter (OTC) and prescription preparations—the minor analgesics salicylic acid and APAP are widely marketed and heavily consumed. Minor analgesics for acute and chronic pain include a number of prescription and OTC agents, which may be useful in isolation or as adjuvants in a more comprehensive multimodal pharmacologic approach. Adjuvants refer to agents that enhance the effect of other medications but may not be fully effective when used alone. A population survey has reported that the use of OTC medications, many of which include minor analgesics, account for the most common method of relieving pain (53%). This is closely followed by physical exercise (52%) and prescription medications (35%).
The minor analgesics reviewed in this chapter include oral APAP, opioid combination preparations, tramadol, steroids, and caffeine, as well as topical compounds and delivery systems ( Box 37.1 ). See the chapters in this text that discuss opioids, anticonvulsants, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) for complete information on these topics ( Chapter 36, Chapter 38, Chapter 39, Chapter 40 ). Additional combination OTC formulations with minor analgesics include convenience combinations—those that contain aspirin, APAP, or ibuprofen plus other remedies such as nasal decongestants, antihistamines, cough suppressants, or antacids. These medications are useful for treating the sequelae of a primary illness (e.g., cold and flu symptoms, insomnia, cough) and any pain symptoms that may coexist.
Minor opioids and combination products
Acetaminophen
Tramadol
Oral steroids
Caffeine and combination products
Topical medications (analgesics, rubefacients, local anesthetics, cooling agents, heating agents)
Over-the-counter convenience products
Prescribing habits regarding the use of analgesics for the treatment of various musculoskeletal conditions continue to evolve. Caudill-Slosberg and colleagues compared prescribing habits between 1980 and 1981 with those between 1999 and 2000 and demonstrated a significant increase in patients receiving prescriptions for acute and chronic musculoskeletal pain. Increases were seen in the use of NSAIDs and cyclooxygenase-2 (COX-2) agents, as well as more potent opioids, including combination opioid preparations containing APAP and NSAIDs.
Minor analgesics are used widely, with reported prevalence rates of twice-weekly use of approximately 8.7% for prescription drugs and 8.8% for OTC analgesics. Analgesics have been found to be the largest selling group of OTC medications in a number of population studies. Daily use was more common for prescribed analgesics, whereas OTC analgesics were used a few times per week. Among prescription and OTC medications, APAP, ibuprofen, and aspirin were the most commonly used (17% to 23% of the population). Use of analgesics, many of which include minor agents, accounts for a significant amount of health care dollars. In a recent population study, analgesic cost ranked second behind diagnostic imaging in expenditures for the treatment of acute low back pain. Chronic use of prescription and OTC analgesics (i.e., aspirin, non–aspirin-containing NSAIDs, and APAP) may continue for longer than 1 year. In the same survey, approximately 2.3 million adults reported using non–aspirin-containing NSAIDs and 2.6 million used APAP on a frequent basis for longer than 5 years. This widespread use occurs despite general knowledge of the increased risk for gastrointestinal (GI), renal, and cardiac toxicity with short-term and chronic use. Unfortunately, the perception remains that as a class of medications, OTC and prescription NSAIDs are relatively safe. This misbelief leads to frequent inappropriate use and the potential for serious adverse events. The increased availability and marketing of OTC agents has probably contributed to patient misuse, with consumers still being unaware of the potential catastrophic risks associated with their use—60% of people cannot identify the active ingredient in their analgesics, and 40% of Americans believe that OTC drugs are too weak to cause significant harm.
The use of OTC and prescription analgesics is not only confined to the outpatient setting. Significant use of these agents in nursing home facilities was reported in a group of Medicare beneficiaries during 2001. Patients averaged 8.8 unique medications per month, including 2.9 OTC medications. Of these subjects, 70% used nonopioid OTC analgesics and 19.0% used nonopioid prescription analgesics.
Specific Drugs
Minor Opioids
In this chapter, minor opioids are defined as analgesic combination products with codeine, hydrocodone, or oxycodone. These products continue to account for a large percentage of prescriptions written for chronic nonmalignant pain. Combination opioid analgesics—compounds containing APAP or anti-inflammatory medications—make up a significant amount of opioids prescribed by primary care physicians and pain specialists. Combination analgesics are advocated in several treatment guidelines, including the three-step analgesic ladder of the World Health Organization (step 2) ( Fig. 37.1 ). Since the 1990s, the use of minor analgesic combinations containing oxycodone and hydrocodone has continued to increase, whereas the use of those containing codeine has declined. Clinic type (e.g., primary care, spine center, pain center), geographic, and socioeconomic variables may also affect prescribing practices.
Opioid analgesics as a class can be categorized into three chemical groups: (1) synthetic phenylpiperidines (e.g., meperidine, fentanyl), (2) synthetic pseudopiperidines (e.g., methadone, propoxyphene), and (3) naturally occurring alkaloids derived directly from the poppy seed (e.g., heroin, morphine, codeine) and their semisynthetic derivatives (e.g., hydromorphone, oxycodone, oxymorphone). This chapter reviews codeine, oxycodone, hydrocodone, and tramadol, all natural or synthetic opioids used in isolation or in combination forms for the treatment of mild to moderate pain ( Tables 37.1 and 37.2 ).
| Class | Name | Adult Dose | Half-Life (Onset) | Mechanism of Action | Other |
|---|---|---|---|---|---|
| Natural opium alkaloids | Codeine with acetaminophen (APAP) or acetylsalicylic acid (ASA) (Tylenol No. 2, No. 3, No. 4; Empirin No. 3, No. 4; Capital with Codeine; Aceta with Codeine; Fioricet with Codeine; Fiorinal with Codeine) | PO: 15-60 mg q4h (max daily APAP-ASA dose, 4 g) | 2.5-3.5 hr (30-60 min) | Opioid agonist activity at multiple receptors—µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects) | Compared with morphine—decreased analgesia, constipation, respiratory distress, sedation, emesis, and physical dependence; increased antitussive effects |
| Phenanthrene derivatives | Hydrocodone plus ASA or APAP (Lortab, Lortab ASA, Vicodin, Norco, Vicoprofen, ZTuss, P-V-Tussin, Tussafed HC) | PO: 5-10 mg q4-6h (max dose, 4 g) | 3.8 hr (10-30 min) | Opioid agonist activity at multiple receptors—µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects) | Compared with morphine-equivalent analgesia—respiratory depression and physical dependency; equivalent antitussive effects |
| Oxycodone (with or without APAP or ASA) (OxyIR, Roxicodone) Oxycodone plus ASA (Percodan, Endodan, Roxiprin) Oxycodone plus APAP (Percocet, Endocet, Tylox, Roxicet, Roxilox) | PO: 5-30 mg q4-6h (4-g max dose of ASA/APAP); sustained release: 10/10-160 mg q12h | 2-5 hr (10-15 min) | Opioid agonist activity at multiple receptors: µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects) | Compared with morphine— more potent analgesia, constipation, antitussive effects, respiratory depression, sedation, emesis, and physical dependence | |
| Diphenylheptane derivative | Propoxyphene, with or without APAP (Darvon, Darvon-N) Propoxyphene plus APAP (Darvocet A500, Propacet 100) | PO: 65 mg q4h (max, 390 mg/day); napsylate, 100 mg q4h (max, 600 mg/day) | 6-12 hr (15-60 min) | Opioid agonist activity at multiple receptors: µ (supraspinal analgesia, euphoria), κ (spinal analgesia and sedation), δ (dysphoria, psychotomimetic effects) | Compared with morphine — less analgesia, sedation, emesis, respiratory depression, and physical dependence |
| Drug Class | Drug Name | Trade Name | Available Dose | Typical Dose | Comments | Half-Life |
|---|---|---|---|---|---|---|
| Para-aminophenol derivatives/natural opium alkaloids | Acetaminophen/codeine phosphate | Tylenol with Codeine elixir; Tylenol with Codeine No. 2, No. 3, No. 4. | (120/12 mg)/5 mL liquid; 300/15 mg, 300/30 mg, 300/60 mg (tablets) | Elixir—children <3 yr, safe dose not established; 3-6 yr, 5 mL (1 tsp) 3-4 times daily; 7-12 yr, 10 mL 3-4 times daily; adults, 15 mL q4h; tablets and capsules, 15-60 mg codeine q4-6h | Codeine phosphate, max, 360 mg daily; acetaminophen, max, 4000 mg daily | Acetaminophen, 1-4 hr; codeine, 2.5-3 hr |
| 650/30 mg (tablets) | 30-60 mg codeine q4-6h | Codeine phosphate, max, 360 mg daily; acetaminophen, max, 4000 mg daily | Acetaminophen, 1-4 hr; codeine, 2.5-3 hr | |||
| Acetylsalicylic acid/natural opium alkaloids | Aspirin/codeine phosphate | Empirin with Codeine No. 3, No. 4 | 325/30 mg, 325/60 mg (tablets) | 1-2 tablets q4h | Codeine phosphate, max, 360 mg daily | Aspirin, 2.5-3.5 hr; codeine, 2.5-3 hr |
| Para-aminophenol derivatives/phenanthrene derivatives | Hydrocodone bitartrate/acetaminophen | Vicodin, Lorcet-HD, Lortab, Norco, Maxidone, Anexsia | 2.5/500 mg, 5/500 mg, 7.5/325 mg, 7.5/500 mg, 7.5/650 mg, 7.5/750 mg, 10/325 mg, 10/500 mg, 10/650 mg, 10/660 mg, 10/750 mg (tablets) | 1-2 tablets q4-6h | Dosage typically limited by acetaminophen, max, 4000 mg daily | Hydrocodone, 3.5-4.1 hr |
| Oxycodone/acetaminophen | Percocet, Endocet, Tylox, Roxicet, Roxilox | 5/325 mg, 7.5/325 mg, 5/500 mg (Tylox), 7.5/500 mg, 10/325 mg, 10/650 mg (tablets); 5/500 mg (caplets; Roxicet); 5/325 mg/5 mL (solution) (Roxicet) | 1-2 tablets q4-6h | Acetaminophen, max, 4000 mg daily | Acetaminophen, 1-4 hr; oxycodone, 3.1-3.7 hr | |
| Acetylsalicylic acid/phenanthrene derivates | Oxycodone/aspirin | Percodan, Endodan, Roxiprin | 4.8/325 mg (tablet) | 1 tablet q4-6h | Aspirin, max, 4000 mg daily | Aspirin, 2.5-3.5 hr; oxycodone, 3.1-3.7 hr |
| Propionic acid/phenanthrene derivatives | Hydrocodone bitartrate/ibuprofen | Vicoprofen | 7.5/200 mg (tablet) | 1 tablet q4-6h | Marketed for short-term management of acute pain; NSAIDs may increase risk for serious cardiovascular thrombotic events, myocardial infarction, stroke | Hydrocodone, 3.5-4.1 hr; ibuprofen, 4-6 hr |
| Oxycodone/ibuprofen | Combunox | 5/400 mg (tablet) | 1-2 tablets q4-6h | Max dosage of ibuprofen, 2400-3200 mg daily | Oxycodone, 3.1-3.7 hr; ibuprofen, 1.8-2.6 hr | |
| Diphenylheptane derivatives | Propoxyphene HC1/APAP | 65/650 mg (tablet) | 1 tablet q4-6h | Structurally related to methadone; propoxyphene HC1, max, 390 mg daily | Propoxyphene, 6-12 hr; norpropoxyphene, 30-36 hr; acetaminophen, 1-4 hr | |
| Propoxyphene HC1/aspirin/caffeine | Darvon Compound 65 | 65/389/32.4 mg (tablet) | 1-2 tablets q4-6h | Structurally related to methadone; propoxyphene HC1, max, 390 mg daily | Propoxyphene, 6-12 hr; norpropoxyphene, 30-36 hr; aspirin, 2.5-3.5 hr, caffeine, 3-6 hr | |
| Propoxyphene napsylate/acetaminophen | Darvocet-N 50, Darvocet-N 100, Darvocet A500, Propacet 100 | 50/325 mg (N 50), 100/650 mg (N 100), 100/500 mg (A500) (tablets) | 1-2 tablets q4-6h | Structurally related to methadone; propoxyphene napsylate, max, 600 mg daily | Propoxyphene, 6-12 hr; norpropoxyphene, 30-36 hr; acetaminophen, 1-4 hr |
Pharmacokinetics and Pharmacodynamics
An understanding of pharmacokinetics and pharmacodynamics is essential for appropriately prescribing minor opioid analgesics, interpreting related toxicology screens, and appreciating the potential mechanisms for adverse side effects. In general, medications are primarily metabolized by the cytochrome P-450 (CYP) and glucuronidation pathways. Opioid analgesics, like any medication, may be metabolized by the CYP drug-metabolizing enzyme system 2D6. Genetic polymorphism of CYP2D6 may lead to variability in enzyme breakdown and clinical effectiveness of the medication. Deficiency of CYP2D6 may be seen in whites (7%) and those of Asian descent (1%). These enzyme systems can be induced (activated) or inhibited by various agents, including drugs, alcohol, and cigarette smoke, as well as by endogenous substances. Inducers are agents that activate the CYP enzyme system and thereby lead to increased metabolism and reduced drug effect. Inhibitors may impair the CYP enzyme system and thus limit metabolism of the drug and increase the effect of the drug. Although pharmacokinetic drug-drug interactions may affect serum levels of a drug, this may be subclinical in most patients, with significant interactions occurring rarely in vivo in only about 10% to 15% of patients. Patients’ response to individual opioids may vary markedly. Recent evidence has supported more than one mechanism for µ-opioid analgesic reactions, which may be related to receptor polymorphism.
Morphine, hydromorphone, and oxymorphone are not metabolized by CYP but are metabolized by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Except for morphine and codeine, UGT enzymes metabolize medications primarily to inactive metabolites. Morphine is converted into large quantities of relatively inactive morphine-3-glucuronide (M3G) and smaller quantities of the active metabolite morphine-6-glucuronide (M6G). M6G is 50 times more potent than morphine. M3G may account for central nervous system (CNS) toxicity, including lowering of seizure thresholds. Equianalgesic oral doses of the various minor opioid combination products and morphine are listed in Table 37.3 .
| Agent | Onset (min) | Duration of Action (hr) | Equianalgesic Oral Dose (mg) ∗ | DEA Schedule |
|---|---|---|---|---|
| Oxycodone combinations | 10-15 | 4-6 | 30 † | II |
| Hydrocodone combinations | 30-60 | 4-6 | 30 | III |
| Codeine combinations | 30-60 | 4-6 | 130 | III |
| Propoxyphene combinations | 15-60 | 4-6 | 130 | IV |
| Tramadol combinations | 60 | 6-7 | 100 | Not scheduled |
∗ Doses reflect the opioid component only and are equianalgesic to 30 mg morphine.
† Doses for moderate to severe pain not necessarily equivalent to 30 mg morphine.
Codeine
Along with morphine and thebaine, codeine (methylmorphine) is a naturally occurring opium alkaloid derivative. A weak analgesic, codeine is similar in structure to morphine but has affinity for the µ-opioid receptor that is 300 times lower. Classically, codeine is thought to be metabolized by O -demethylation to its primary active metabolite morphine by the CYP2D6 enzyme. Studies have demonstrated that only a small percentage of the total dose (3%) is converted by CYP2D6 to morphine. Approximately 80% is directly glucuronidated by uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) enzyme to codeine-6-glucuronide (C6G), an additional active metabolite. The remaining inactive metabolites are primarily norcodeine (2%) and normorphine (2.4%). Nonfunctional CYP2D6 renders codeine ineffective, perhaps because of genetic mutations or deletions or pharmacologic inhibition. Effects of codeine not related to the formation of morphine include cognitive impairment, sedation, dizziness, euphoria and dysphoria, headache, blurred vision, and prolongation of GI transit time. The average half-life of codeine is 2.5 hours.
Efficacy
When used alone, codeine is typically prescribed in doses of 30 to 60 mg every 4 to 6 hours, with onset of analgesia taking place in 30 to 60 minutes and the duration of effect lasting 4 to 6 hours.
Codeine has been shown to be an effective cough suppressant (10 to 120 mg/day) and is present in a number of OTC cold and cough convenience preparations. However, codeine’s potential opioid analgesic effect has long been questioned. Houde’s classic study in the 1960s reported the analgesic effects of codeine (32 mg) to be no more than that of 650 mg of aspirin, although both were more effective than placebo. The number needed to treat (NNT), or the number of patients needed to receive the medication to achieve at least 50% pain relief, with 60 mg codeine has been reported to be 16.7, which has led to its widespread use as a combination analgesic.
Codeine (10 to 60 mg) is more commonly prescribed in combination with APAP (400 to 1000 mg), aspirin, or NSAIDs such as ibuprofen (400 mg). A systematic review of codeine and APAP trials for acute non–cancer-related pain concluded that the benefit over codeine alone is only modest (5%). A systematic review of trials of APAP alone or in combination with codeine noted efficacy in patients prescribed APAP plus 60 mg codeine versus APAP alone. At doses higher than 60 mg, there was diminishing incremental analgesia with increasing dose and a higher incidence of side effects (e.g., constipation, nausea, and sedation). A head-to-head study of codeine (30 mg) plus APAP (300 mg) and hydrocodone (7.5 mg) plus APAP (500 mg) showed significant relief of moderate to severe acute (6 hours) postoperative pain in comparison to placebo, but the analgesia was no greater than that achieved with hydrocodone-APAP.
Propoxyphene (Dextropropoxyphene)
Propoxyphene (dextropropoxyphene) is a mild synthetic opioid originally synthesized in the 1950s and primarily marketed in its hydrochloride form as Darvon (65 mg; maximum, 400 mg/day), as propoxyphene napsylate (Darvocet-N 50, Darvocet-N 100), and in Europe, as co-proxamol (32.5 mg dextropropoxyphene plus 325 mg paracetamol). By the late 1960s, propoxyphene was the most widely prescribed analgesic in the United States. Reports of propoxyphene overdoses led to warnings by the U.S. Food and Drug Administration (FDA) in 1978 and a subsequent reduction in use. Use of propoxyphene continued for a number of years, primarily in older adults, because of its perceived safety profile. However, Smith suggested that its analgesic activity is lower than that of aspirin. Propoxyphene’s major metabolite norpropoxyphene has fewer CNS effects than propoxyphene does but accumulates in cardiac tissue, thereby leading to a local anesthetic effect and prolongation of action potentials, in some cases fatal torsades de pointes. Because of the increasing number of fatal overdoses of co-proxamol and limited evidence supporting its efficacy versus APAP for acute and chronic pain, the British government announced the gradual withdrawal of co-proxamol from British markets in January 2005. As a result of increasing public outcry from patient advocacy groups and recommendations by an FDA advisory board group, propoxyphene was voluntarily removed from the U.S. market in 2011 (Propoxyphene: withdrawal—risk of cardiac toxicity. Available at www.fda.gov/Safety/MedWatch/SafetyInformation/…/ucm234389.ht . Accessed August 28, 2012). It is interesting to note that at the time of its withdrawal from the market, a survey showed that 68% of pain medicine practitioners saw patients who were prescribed propoxyphene by their primary care physicians.
Oxycodone
Oxycodone is a semisynthetic opioid analgesic derived from the opium alkaloid thebaine. Human studies have demonstrated it to have analgesic potency 1.5 times that of morphine after oral administration. A number of active metabolites have been proposed to contribute to the clinical pharmacokinetics of oxycodone. One theory supports 3- O -demethylation by CYP2D6 to oxymorphone. Oxymorphone is a potent µ-opioid ligand with two to five times higher receptor affinity than morphine has. Though potent, oxymorphone accounts for only 10% of oxycodone metabolites. Oxymorphone has been available for a number of years for parenteral and rectal use and was reformulated and released in an immediate-release (IR) and extended-release (ER) schedule II formulation. In vitro studies have shown that O -demethylation of oxycodone accounts for 13% of its oxidative metabolism. Oxidation of oxycodone primarily occurs via N -demethylation by CYP3A4/5 to noroxycodone, which is the most abundant circulating metabolite in human studies. Unfortunately, noroxycodone has weak affinity for µ-opioid receptors.
In vivo, oxycodone has potent µ-opioid receptor effects, but data suggest that the intrinsic antinociceptive effects may be additionally mediated by κ-opioid receptors. This has led some to consider oxycodone an ideal medication for opioid rotation in patients not responsive to morphine, a classic µ-opioid receptor agonist. Recent studies have proposed non-CYP2D6 metabolites (noroxycodone, noroxymorphone, noroxycodols, oxycodols) as additional substances responsible for its µ-opioid receptor binding and analgesic effects. Animal studies have recently demonstrated conflicting gender-related differences in female versus male rats when examining the antinociceptive effects of oxycodone.
Hydrocodone
Hydrocodone is similar in structure to codeine but is six to eight times more potent. Hydrocodone is a prodrug and undergoes CYP2D6 metabolism to hydromorphone and CYP3A4 metabolism to noroxycodone. Hydrocodone is less potent than morphine by receptor affinity and demonstrates a relative analgesic potency of 0.59 in comparison to morphine. The discrepancy between hydrocodone’s binding affinity and potency versus that of morphine is possibly the result of active hydrocodone metabolites or the intrinsic efficacy of receptor activation, which is more efficient for hydrocodone than for morphine. Hydrocodone is marketed as a combination product with APAP, ibuprofen, and aspirin.
Efficacy
The hydrocodone-ibuprofen combination product was introduced in the United States in 1997 as a fixed dose of hydrocodone (7.5 mg) and ibuprofen (200 mg) and has demonstrated efficacy for acute postoperative pain. Neither hydrocodone (7.5 mg) nor ibuprofen (200 mg) given alone was superior to placebo, thus supporting the concept of analgesic synergy between the two agents. Similar findings were demonstrated in patients with acute low back pain and postoperative obstetric and gynecologic pain. Hydrocodone-APAP (7.5, 200 mg), one and two tablets, was compared with a fixed-dose combination of codeine (30 mg) and APAP (300 mg). The two-tablet dose of combination hydrocodone-APAP was more effective than the one-tablet dose and one or two tablets of the fixed codeine-APAP combination.
In 2010, more than 139 million prescriptions for hydrocodone combination products (APAP, ibuprofen) were dispensed in the United States (Drug Enforcement Administration. Hydrocodone, June 2011. Available at: www.deadiversion.usdoj.gov/drugs_concern/hydrocodone.pdf . Accessed June 11, 2012.). Hydrocodone-APAP combination products are classified as schedule III controlled substances. Pure hydrocodone is schedule II but is not presently commercially available in the United States (Code of Federal Regulations. Title 21: Food and Drugs Part 1308; Schedules of Controlled Substances 1308.13; Schedule III, June 2012.). Because of high rates of misuse and abuse of hydrocodone products, the U.S. House of Representatives is considering legislation that would reclassify all products containing hydrocodone from schedule III to schedule II. As a result of increasing reported toxicity of APAP in combination opioid and OTC products, the U.S. FDA has mandated a reduction in APAP in combination opioid products by 2014. Reformulations of these products will include a maximum of 300 mg of APAP (Abbott Laboratories, 2012). Commonly prescribed hydrocodone-APAP combination products presently include 10, 7.5, and 5 mg hydrocodone and 325, 500, 750 mg APAP, with ranges between 5 and 10 mg hydrocodone and 325 and 750 mg APAP (Hydrocodone Bitartrate/Acetaminophen Tablets, package insert, Mallinckrodt, Inc., St. Louis).
Pipeline hydrocodone formulations in development include an ER hydrocodone product (hydrocodone bitartrate ER capsules [Zohydro], Zogenix, Inc., San Diego. Available at www.zpgenix.com/index/php/products/zx002 . Accessed June 11, 2012) and a tamper-resistant (Teva Pharmaceuticals) long-acting formulation. A “tamper-deterrent” pure hydrocodone product with approximately 45 mg hydrocodone is also in development (Teva Pharmaceuticals).
Acetaminophen
APAP (paracetamol) and APAP combination products (i.e., containing opioids) are commonly prescribed as a minor analgesic for acute and chronic pain (see Table 37.2 ). The American College of Rheumatology and similar European professional colleges have recommended it as first-line pharmacologic therapy for osteoarthritis (OA). Prescription APAP is available as an opioid-containing combination product (e.g., codeine, hydrocodone, oxycodone), whereas OTC preparations may be combined with pseudoephedrine or dextromethorphan as convenience drugs.
Mechanism of Action and Description
APAP (paracetamol) is a p -aminophenol analgesic that was introduced in the late 1800s in Germany, a product of the rapidly developing chemical industry. Newly synthesized compounds included synthetic antipyretics and analgesics such as acetophenetidin (phenacetin), antipyrine (phenazone), and acetylsalicylic acid (ASA; aspirin). Paracetamol, the active metabolite of phenacetin, was found to demonstrate less intense GI side effects, which led to its use as an analgesic. Paracetamol was formally introduced in the United States in the 1950s, and though found in the 1960s to have hepatotoxic effects with unintentional misuse and overdose, it became one of the most widely used OTC and combination prescription analgesics worldwide.
Although APAP has been in use since the 1890s, its pharmacologic mechanism of action remains unclear. Generally, it has known analgesic and antipyretic activity with no known peripheral anti-inflammatory or platelet effects. Its antipyretic activity may be secondary to blockade of prostaglandin (PG) production and inhibition of PG endoperoxide H 2 synthase and COX centrally. APAP may block COX activity by reducing the active form of COX to an inactive form, but with only limited effects in the GI tract and peripherally at sites of inflammation, thus contributing to a lower GI side effect profile than that of NSAIDs. Also, recent studies have suggested that its central analgesic qualities may be related to decreased activation of a subtype of endogenous opioid peptide, β-endorphin.
APAP is available in oral and rectal formulations and is rapidly absorbed from the GI tract, mainly the small intestine. APAP has a half-life (t ½ ) of between 1.25 and 3 hours and serum therapeutic levels of 10 to 30 µg/mL. Twenty-five percent of the dose undergoes first-pass metabolism in the liver. Up to 90% of APAP is metabolized in the liver via glucuronidation and sulfate conjugation to nontoxic metabolites. The remaining 10% undergoes oxidative metabolism via the CYP system (CYP2E1 and CYP1A2), which is responsible for formation of the potentially hepatotoxic and nephrotoxic metabolite N -acetyl- p -benzoquinoneimine (NAPQI; Fig. 37.2 ). This minor pathway becomes more critical when the enzyme system responsible for sulfonation and glucuronidation becomes saturated with doses higher than 150 mg/kg, thereby increasing the total fraction of NAPQI. Approximately 85% of the dose is excreted in urine within 24 hours of oral dosing. NAPQI is itself detoxified by conjugation with glutathione. Case reports have suggested that clinical situations characterized by low glutathione levels (e.g., chronic hepatitis C, malnourishment, human immunodeficiency virus infection, cirrhosis) may place these patients at greater risk for adverse events from APAP. However, one study found no significant evidence that these populations are at higher risk for APAP toxicity. There are few clinically significant pharmacokinetic interactions with therapeutic doses of APAP. Although case reports have attributed an elevated international normalized ratio (INR) to APAP and oral anticoagulant drug interactions, randomized controlled studies have found no evidence of clinically significant changes in the INR. Even though studies have demonstrated an association, there is no clear evidence of cause and effect.
Risks and Precautions
APAP-induced toxicity is often associated with liver and renal dysfunction. APAP hypersensitivity reactions are rare, but severe reactions are possible. In general, chronic administration of APAP may cause depletion of glutathione stores and hence lead to greater production of the hepatotoxic and nephrotoxic metabolite NAPQI. Current recommendations for a maximum daily dosage of APAP are approximately 4 g/day in adults and 75 mg/kg/day in infants and children ( Box 37.2 ). Unintentional liver injury, such as hepatic necrosis or acute liver failure from self-medication with OTC and prescription APAP products, can develop with dosages exceeding 4 g/day.
Dosing for Mild Pain
- •
325-1000 mg PO, per rectum, q4-6h
- •
Maximum dose: 1 g/dose; 4 g/24 hr
- •
American Liver Foundation: patients should not exceed 3 g/day for any prolonged period ∗
∗ Based on a recent study by Watkins and Seeff.
Renal Impairment
- •
Adjust dose frequency
- •
Creatine clearance (CrCl) = 10-50 mL/min, q6h; CrCl < 10 mL/min, q8h
Hepatic Impairment
- •
Use with caution
- •
Consider decreasing the dose, monitor liver function, avoid chronic use
Counseling Patients
Acetaminophen (APAP) in over-the-counter products:
- •
Regular-strength APAP products commonly contain 325 mg/tablet
- •
Extra-strength APAP products commonly contain 500 mg/tablet
- •
The serum alanine transaminase (ALT) level may be elevated with acute use of recommended doses of APAP. Watkins and Seeff studied healthy adults given 4 g of APAP for 14 days. They found that 31% to 44% of the study subjects, which included patients taking APAP and various opioid-APAP combination products, demonstrated elevations to three times the upper limit of normal (typically considered clinically significant). Opioids were found to have no additional effect on ALT levels. Elevated liver function is not routinely seen with chronic use and is thought to occur because of cellular adaptation. This APAP tolerance may be characterized by possible downregulation of CYP bioactivation and increases in glutathione production by liver hepatocytes.
The concomitant use of alcohol and APAP resulting in increased risk, lower threshold for hepatic and renal toxicity, or both remains controversial and has been reported primarily in retrospective reviews and case reports. Acute and chronic alcohol use contributes to drug-induced hepatotoxicity via induction of CYP2E1 and NAPQI formation. Enhanced ethanol-related toxicity was demonstrated only in patients at high risk with APAP levels above 300 mg/mL, a level far above the package insert recommendation for no more than three alcoholic beverages daily. When consumed with APAP, ethanol may block the formation of NAPQI. Other inducers of hepatic isoenzymes CYP2E1 and CYP1A2 that are commonly used for pain management include carbamazepine, oxcarbazepine, barbiturates, and phenytoin ( Box 37.3 ). Most importantly, the risk for APAP-induced hepatotoxicity may be increased in patients with alcoholic hepatic disease, viral hepatitis, or alcoholism because of a reduction in glucuronide conjugation and subsequent depletion of glutathione reserves.
Serotonin (5-HT) Reuptake Inhibitors
Paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram
Venlafaxine, milnacipran, duloxetine
Clomipramine, imipramine
Tramadol, meperidine, fentanyl, methadone, dextromethorphan, dextropropoxyphene
Serotonin Precursors
5-Hydroxytryptophan, l -tryptophan
5-HT 1A Antagonists
LSD, dihydroergotamine, bromocriptine, buspirone
Serotonin Releasers
Amphetamine, MDMA (“ecstasy”)
Monoamine Oxidase Inhibitors
Tranylcypromine, phenelzine, nialamide, isoniazid, iproniazid, isocarboxazid
Pargyline, selegiline, procarbazine
Moclobemide
Chronic APAP prescribing should be avoided in patients with renal disease, although the exact mechanism of injury is unknown and may be relevant only in patients with preexisting renal compromise or systemic disease. Patients with a history of salicylate hypersensitivity characterized by drug-induced urticaria have demonstrated 11% cross-reactivity to APAP. APAP use has been shown to be associated with hypertension in two large prospective studies in women. Similar studies in healthy men failed to show an association with use of APAP and hypertension. Analgesics, in general, may modestly affect blood pressure via a number of mechanisms, primarily through kidney or systemic COX-2 inhibition of PGs, which leads to an imbalance between the vasodilators PGI 2 and PGE 2 and the vasoconstrictors PGF 2α and thromboxane A 2 . These effects on PG synthesis are greater with NSAIDs than with APAP.
Clinical Use
Although a number of guidelines have recommended APAP as a first-line agent, its advantages over NSAIDs in managing OA-related pain remain controversial. A double-blind trial of paracetamol, 4 g/day, for 1 month found it to be as effective as both analgesic and anti-inflammatory doses of ibuprofen in patients with knee OA. More recent studies have demonstrated the efficacy of both a traditional NSAID (diclofenac) and a COX-2 inhibitor (celecoxib) versus APAP in hip and knee OA cohorts. A Cochrane database review of the use of APAP for the chronic pain of OA found the drug to be less effective than NSAIDs in terms of pain reduction scores, although the superiority of NSAIDs over APAP appeared to be more evident in OA patients with more severe pain. Both the NSAID and APAP groups had similar efficacy with regard to functional status. Recent evidence has suggested that APAP may retain anti-inflammatory action comparable to that of NSAIDs in patients with knee OA. Brandt and associates performed a pilot study of 30 subjects in whom OA of the knee was diagnosed and showed that treatment with APAP results in similar significant decreases in mean total knee effusion volume (measured by magnetic resonance imaging) as does treatment with NSAIDs.
Tramadol
Tramadol, (±)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol hydrochloride, is a synthetic racemic mixture typically used for its centrally acting analgesic properties. However, clinical and basic science studies have described numerous mechanisms of action at central and peripheral sites. Tramadol is classified as a weak synthetic opioid with mild serotonin and norepinephrine reuptake–inhibiting effects.
Mechanism of Action and Description
The most well-studied mechanism of action of tramadol is its weak affinity for opioid receptors, the most significant of which involves the µ receptor. However, tramadol-induced analgesia is only partially inhibited by the opiate antagonist naloxone, thus suggesting additional non–opioid-related analgesic mechanisms. Tramadol also displays an inhibitory effect on the central neuronal norepinephrine and serotonin (5-HT) reuptake systems. More recently, noted actions include a local anesthetic effect, anti-inflammatory effects in rat experimental models, and reduction of substance P levels in human synovial fluid. Although α 2 -agonist activity has also been reported, concentrations in the range of 10 to 100 µmol/L do not bind significantly to α 2 -adrenergic receptors.
Opioid Receptors
Tramadol’s affinity for the µ receptor appears to be approximately 10 times weaker than that of codeine, 60 times weaker than that of dextropropoxyphene, and 6000 times weaker than that of morphine ( Table 37.4 ). The active O -demethylated metabolite M1 has 300 times higher affinity for the µ receptor than the parent compound does and is up to six times more potent in producing analgesia.
| Drug | K i Values (mmol/L) | ||
|---|---|---|---|
| µ Receptor | δ Receptor | κ Receptor | |
| Morphine | 0.00034 | 0.092 | 0.66 |
| Dextropropoxyphene | 0.034 | 0.38 | 1.22 |
| Codeine | 0.2 | 5.1 | 6.0 |
| Tramadol | 2.1 | 57.6 | 42.7 |
| Imipramine | 3.7 | 12.7 | 1.8 |
Central Neuronal Actions
Multiple actions affecting the descending inhibitory pain pathways have been reported. The first system involves neurons originating in the periaqueductal gray matter in the midbrain that synapse at the nucleus raphe magnus, from which fibers then project to the spinal cord. Inhibition of 5-HT reuptake may contribute to inhibition of pain. Another pathway originates at the locus coeruleus in the pons, with fibers projecting to the spinal cord. The norepinephrine released from this pathway inhibits pain responses at the spinal cord via an α-adrenergic mechanism.
Activation of these descending pain inhibition pathways stimulates interneurons that inhibit the transmission of painful stimuli in the dorsal horn by the action of endogenous opioids. Opioid receptor activity has been proposed to be mediated by the dextrorotatory (+) enantiomer as opposed to the levorotatory (−) enantiomer. The (−) enantiomer is approximately 10 times more potent than its (+) counterpart in the inhibition of norepinephrine uptake, and the (+) enantiomer is approximately 4 times more potent than the (−) enantiomer in the inhibition of 5-HT uptake. M1 retains higher affinity for the µ-opioid receptor (300 to 400 times) and possesses greater analgesic activity than the parent compound does. The M1 (+) enantiomer acts at the µ receptor, whereas the M1 (−) enantiomer mainly inhibits reuptake of norepinephrine ( Table 37.5 ).
| Product | Affinity for Opioid Receptors (K i , mmol/L) | Reuptake Inhibition | |||
|---|---|---|---|---|---|
| µ | δ | κ | Norepinephrine | Serotonin | |
| (±) Tramadol | 2.1 | 57.6 | 42.7 | 0.78 | 0.9 |
| (+) Tramadol | 1.3 | 62.4 | 54.0 | 2.51 | 0.53 |
| (−) Tramadol | 24.8 | 213 | 53.5 | 0.43 | 2.35 |
| (+) M1 | 0.0034 | ||||
| Morphine | 0.00034 | 0.092 | 0.57 | Inactive | Inactive |
| Imipramine | 3.7 | 12.7 | 1.8 | 0.0066 | 0.021 |
Formulations include IR and sustained-release (SR) oral forms (SR, dosing every 12 hours; ER, dosing every 24 hours); injectable solutions for subcutaneous, intravenous, spinal, or intramuscular administration; and a rectal formulation. SR formulations are available in a number of countries worldwide, but only the ER formulation is currently available in the United States. In addition, an orally disintegrating tablet version of tramadol (Ralivia FlashDose) for the treatment of moderate to moderately severe pain is under development. Tramadol is currently recommended for the treatment of moderate to moderately severe pain in patients unresponsive to previous oral therapies or who have a contraindication to COX-2–selective or COX-2–nonselective NSAIDs.
History
Tramadol has been available in Germany since 1977, where it remains one of the most widely prescribed analgesics. Before its U.S. release in 1995, clinical and epidemiologic studies suggested that tramadol demonstrates low abuse potential, which led the Drug Abuse Advisory Committee to recommend FDA approval of tramadol as a nonscheduled analgesic. Current studies continue to support the low abuse potential of tramadol. A postmarketing survey has demonstrated limited evidence of tramadol use–related dependence, withdrawal, and abuse. Another study assessing the prevalence of abuse compared tramadol with NSAIDs and hydrocodone-containing analgesics in patients with chronic non–cancer-related pain. This study used an abuse index that identified subjects according to the following behavior: (1) increased doses without physician approval, (2) used for purposes other than intended, (3) demonstrated an inability to stop use, and (4) experienced withdrawal. The percentage of subjects who scored positive (at least one of the four types of behavior) during a 12-month period was 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone.
Formulations
Currently available oral formulations of tramadol include 50-mg scored IR tablets, SR tablets and capsules (every-12-hour dosing available worldwide but not in the United States), two ER once-daily tablets (Ultram ER and Ryzolt [Purdue Pharma]), and combination tablets consisting of tramadol, 37.5 mg, plus APAP, 325 mg. The SR preparations are available in strengths of 50, 100, 150, and 200 mg taken on a twice-daily schedule. ER tramadol hydrochloride tablets (Ultram ER) are available in 100-, 200-, and 300-mg strengths taken on a once-daily basis. The bioavailability of Ultram ER, 200 mg, relative to tramadol, 50-mg IR formulation every 6 hours, is approximately 85% to 90%. Steady-state plasma concentrations of tramadol and M1 are achieved within 4 days of once-daily dosing. Important pharmacokinetic parameters of the 200-mg ER formulation include a time of maximum concentration (T max ) of 12 and 15 hours for tramadol and the M1 metabolite, respectively, as compared with a T max of 1.5 and 1.9 hours for tramadol and the M1 metabolite, respectively, with the 50-mg IR formulation ( Table 37.6 ).
| Pharmacokinetic Parameter | Tramadol | M1 Metabolite | ||
|---|---|---|---|---|
| Ultram ER | Ultram IR | Ultram ER | Ultram IR | |
| C max (µg/L) | 335 | 383 | 95 | 104 |
| C min ((µg/L) | 187 | 228 | 69 | 82 |
| T max (hr) | 12 | 1.5 | 15 | 1.9 |
Once-daily ER Ultram was formulated to counter the need for doses of IR tramadol hydrochloride (Ultram) every 6 hours, improve compliance, and decrease sleep interruptions because of more stable serum concentrations. The bioavailability of ER tramadol is comparable to that of IR tramadol and demonstrates steady-state bioequivalence (area under the plasma drug concentration–vs.-time curve and maximum concentration [C max ] values) when compared with IR tramadol administered four times daily. ER tramadol (200 mg) has a longer T max (tramadol, 12 hours; M1 metabolite, 15 hours) than IR tramadol does (tramadol, 1.5 hours; M1 metabolite, 1.9 hours) but reaches steady-state plasma concentrations (tramadol and M1) within 4 days with once-daily dosing.
ER tramadol (100, 200, 300 mg) was found to be superior to placebo in average change from baseline pain from 1 through 12 weeks in a randomized trial of OA of the knee. The average ER tramadol dose was 276 mg/day.
Tramadol hydrochloride ER tablets (Ryzolt, Purdue Pharma L.P., Stamford, Conn, 2009) contain both IR and ER characteristics (100, 200, and 300 mg). Ryzolt is indicated for the management of moderate to moderately severe chronic pain in adults who require around-the-clock treatment of their pain for an extended period. The median time to peak plasma concentrations of tramadol and M1 after multiple doses of 200-mg tablets is about 4 and 5 hours, respectively. Steady state is achieved after 2 days with a relative bioavailability of approximately 95% with 200 mg of Ryzolt versus IR tramadol, 50 mg every 6 hours (Ryzolt Package Insert, Purdue Pharma L.P., 2009).
Pharmacokinetics
The maximum serum concentration of oral tramadol is reached in approximately 2 hours. Its mean bioavailability after a single dose is 68%, and this increases to 90% to 100% after multiple doses. Mean bioavailability after intramuscular administration is 100% and after rectal administration is 78%. Tramadol is 20% bound to plasma proteins and crosses the placenta. Metabolism is primarily hepatic via the CYP enzyme system. Tramadol is excreted by the kidneys (90%) and in feces (10%). Biotransformation in the liver creates 23 metabolites; the primary metabolite is O -desmethyltramadol (M1). Polymorphism of the CYP2D6 isoenzyme in the liver (present in approximately 7% to 10% of whites) may cause attenuation of analgesia in poor metabolizers. Such patients may require higher loading doses and more rescue analgesia. The elimination t ½ of tramadol is 5 to 6 hours and that of M1 is approximately 8 hours. Adjustments in dosage are required for patients with hepatic and renal failure and for geriatric patients ( Table 37.7 ). Bioequivalence has been demonstrated between IR and SR-ER formulations (see Table 37.6 ).
| Parameter | Young Healthy Volunteers | Older Healthy Volunteers | Patients With Renal Failure (IV, n = 12) | Patients With Hepatic Failure (PO, n = 10) | ||
|---|---|---|---|---|---|---|
| IV ( n = 10) | PO ( n = 10) | PO ( n = 12; age = 65-75 yr) | PO ( n = 8; age >75 yr) | |||
| T max (hr) | — | 1.9 | 2.0 | 2.1 | — | 1.9 |
| C max (µg/L) | 409 | 290 | 324 | 415 | 894 | 433 |
| AUC (µ/L × hr) | 3709 | 2488 | 2508 | 3854 | 7832 | 7848 |
| t ½ β (hr) | 5.2 | 5.1 | 6.1 | 7.0 | 10.8 | 13.3 |
| TC (L/hr) | 28.8 | 42.6 | 47.6 | 29.5 | 16.8 | 16.3 |
∗ Depending on the patient’s age and hepatic and renal failure.
Management Considerations
For improved tolerability of tramadol, various titration regimens have been proposed ( Table 37.8 ). An alternative example of a titration schedule for the IR 50-mg tablets in patients with moderate to moderately severe chronic pain is as follows:
- 1.
Start at 25 mg/day and titrate in 25-mg increments as separate doses every 3 days to reach 100 mg/day (25 mg four times daily).
- 2.
Increase the total daily dose by 50 mg as tolerated every 3 days to reach 200 mg/day (50 mg four times daily).
- 3.
After titration, tramadol, 50 to 100 mg, can be administered as needed for pain relief every 4 to 6 hours, not to exceed 400 mg/day.
| Tramadol Dose (mg) | Day |
|---|---|
| Chronic Pain | |
| 25 q am | 1 |
| 25 bid | 2 |
| 25 tid | 3 |
| 25 qid | 4 |
| 50 q am , 25 noon, 25 afternoon, 50 qhs | 5-7 |
| 50 qid | 8-10 |
| 50-100 qid | 11-X |
| Acute or Subacute Pain | |
| 50 q6h | 1-3 |
| 100 q6h | 4-X |
Patients with moderately severe pain who need more immediate pain control may benefit from a more aggressive dosing schedule. In this case, the increased risk for adverse events associated with higher initial doses must be clearly discussed and acceptable. In this subset of patients, tramadol, 50 to 100 mg, may be administered as needed every 4 to 6 hours, not to exceed 400 mg total per 24-hour period.
The initial recommended dose of tramadol SR formulations is 50 to 100 mg twice daily. Titration to doses of 150 to 200 mg twice daily pending side effect tolerability and efficacy of pain relief as needed may be carried out. Tramadol ER dosage recommendations include an initial dose of 100 mg daily, with upward titration by 100 mg every 5 days to a maximum daily dosage of 300 mg.
Risks and Precautions
When compared with traditional opioid analgesics, tramadol retains a more favorable side effect profile and may be associated with a lower risk for addiction with chronic use.
Common Side Effects
The most commonly reported side effects include nausea, vomiting, dizziness, fatigue, sweating, dry mouth, drowsiness, sedation, and orthostatic hypotension. The incidence of side effects has been reported to be as high as 16.8% in patients with chronic pain complaints. Controlled-release formulations may produce a lower incidence of side effects (6.5%).
Despite its improved side effect profile and early consideration as an alternative to pure µ-opioid receptor agonist medications, reports of overdose and fatality have led to a change in the package insert information that includes a contraindication in patients with a past or present history of addiction or dependence on opioids. Other more severe side effects include angioedema, bleeding complications because of the increased effect of oral anticoagulants, and serotonin toxicity.
Tramadol and Serotonin Toxicity (Serotonin Syndrome)
Concomitant use of tramadol with other serotonergic medications (e.g., selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase inhibitors [MAOIs], and serotonin-norepinephrine reuptake inhibitors [SNRIs]; Box 37.4 ) has been associated with case reports of serotonin toxicity. Given the fact that a number of medication classes commonly used for management of pain may predispose patients to mild to severe symptoms of serotonin toxicity, a review to gain a more clear understanding of serotonin toxicity and serotonin syndrome is in order.
CYP1A2
Barbiturates
Bupropion (possible)
Caffeine
Carbamazepine
Charcoal-broiled food
Cruciferous vegetables
Dihydralazine
Isoniazid
Phenytoin
Primidone
Rifampin
Ritonavir
Sulfinpyrazone
CYP2E1
Ethanol
Isoniazid
Definition
Serotonin toxicity is an iatrogenic drug-induced toxidrome, a group of signs and symptoms occurring together with a particular type of chemical poisoning. Life-threatening serotonin toxicity, though rare, is usually precipitated by ingestion of MAOIs and SSRIs and leads, in some cases, to hyperpyrexia and death. The pathophysiology remains unclear but may involve overstimulation of 5-HT 1A and 5-HT 2 receptors in the brain. Serotonin toxicity has been described by Gillman and Whyte as a triad involving neuromuscular hyperactivity, autonomic hyperactivity, and altered mental status ( Table 37.9 ).
| Parameter | Manifestations |
|---|---|
| Neuromuscular hyperactivity | Tremor, clonus, myoclonus, hyperreflexia |
| Autonomic hyperactivity | Diaphoresis, fever, tachycardia, tachypnea, mydriasis |
| Altered mental status | Agitation, excitement, confusion |
Sternbach proposed criteria for serotonin syndrome in one of the earlier published comprehensive reviews of serotonin syndrome. In 2000, Radomski and associates published an updated review of the subject with revised diagnostic criteria ( Table 37.10 ).
| Mild State of Serotonin-Related Symptoms | Serotonin Syndrome (Full-Blown Form) | Toxic States | |
|---|---|---|---|
| Single symptom may predominate | At least four major or three major and two minor of the following: | Coma | |
| Most common are Tremor Myoclonus Diaphoresis and shivering | Major | Minor | Generalized tonic-clonic seizures Fever (may exceed 40° C) Disseminated intravascular coagulation and renal failure |
| Mental symptoms: Impaired consciousness Elevated mood Neurologic symptoms: Myoclonus Tremor Shivering Rigidity Hyperreflexia Vegetative symptoms: Fever Sweating | Restlessness Insomnia Incoordination Dilated pupils Akathisia Tachycardia Tachypnea, dyspnea Diarrhea Hypertension, hypotension | ||
Mechanisms of Serotonin Toxicity
Serotonin toxicity may be related to the mechanisms and potency of drugs. Tricyclic antidepressants (TCAs) exhibit a 100-fold variability in affinity for the serotonin transporter in humans. Overdose of amitriptyline alone does not precipitate serotonin toxicity. More potent TCAs, such as clomipramine, may actually have more potent serotonergic effects clinically and in overdose. In overdoses of SSRIs or SNRIs such as with venlafaxine alone, 15% of individuals exhibit moderate serotonin toxicity without life-threatening symptoms or pyrexia. Although venlafaxine has less potency than amitriptyline at the receptor level, it precipitates serotonin toxicity more frequently than SSRIs do (30% vs. 15%). This may be related to mechanisms other than inhibition of serotonin reuptake. Trazodone and nefazodone differ from TCAs and SSRIs in that they are primarily 5-HT 2A antagonists. Neither exhibit serotonergic side effects, nor do they induce signs of serotonin toxicity in overdose.
A number of other pharmacologic agents, including illicit substances, enhance 5-HT activity and must be considered in the workup for possible serotonin toxicity (e.g., buspirone, ergot alkaloids, amphetamine, cocaine, TCAs, MAOIs ; see Box 37.3 ).
Clinical Use of Tramadol Formulations
Earlier reports evaluating the effectiveness of tramadol for varied painful conditions yielded conflicting results. In comparative studies of acute pain, oral tramadol was found to have efficacy similar to that of propoxyphene in a postoperative pain study and comparable efficacy as codeine for pain related to dental surgery. However, tramadol hydrochloride, 50 and 100 mg, was found to have efficacy similar to that of placebo for pain after total hip arthroplasty but provided analgesia inferior to that of hydrocodone-APAP in an emergency room acute musculoskeletal pain cohort consisting of fracture, sprain-strain, and contusion.
More recent clinical and evidence-based practice has found tramadol to be useful for a wide range of painful conditions, including OA, postamputation phantom limb and residual limb pain, postoperative pain reduction after arthroscopic knee surgery, and cancer-related pain. Guidelines for the pharmacologic management of OA have recommended tramadol for patients who fail to achieve analgesia with APAP, COX-2 inhibitors, or NSAIDs.
A 2004 Cochrane collaboration review of tramadol for neuropathic pain identified a number of eligible trials, including two comparing tramadol with placebo, one comparing tramadol with clomipramine, and one comparing tramadol with morphine for cancer pain. Tramadol was found to be effective for the treatment of neuropathic pain based on this limited number of short-term studies (4 to 6 weeks). The NNT for tramadol in relieving neuropathic pain states (3.5) was similar to that for other commonly used medications—2.4 for TCAs, 2.5 for carbamazepine, and 3.7 for gabapentin.
Tramadol-Acetaminophen
A number of different strengths of combination tramadol and APAP compounds are available in the United States and Europe. The combination takes advantage of the potential synergy between the two compounds demonstrated in animal and human models, with an initial onset of analgesia with APAP (20 minutes) followed by tramadol (approximately 50 minutes). A meta-analysis of dental pain has demonstrated that the combination of APAP plus tramadol has a similar rapid onset of efficacy as paracetamol alone, but levels of analgesia are maintained for a longer period than with tramadol alone. Tramadol-APAP combination products contain less tramadol by dose (in the United States, 37.5 vs. 50 mg) and relatively less APAP (325 vs. 500 mg [extra-strength APAP]) and thus may lower the potential incidence of organ toxicity (liver) when taken within the range of recommended doses. Tramadol-APAP combination products have demonstrated efficacy for acute and chronic pain conditions. Combination tramadol, 37.5 mg, plus APAP, 325 mg, may provide analgesia equivalent to that of codeine and APAP in patients with chronic OA, but with greater tolerability. The most common treatment-related adverse events include somnolence, nausea, and constipation with a mean dosage of 4.1 tablets daily. Figure 37.3 illustrates NNT data from a meta-analysis evaluating the efficacy of a tramadol-APAP combination for moderate to severe postoperative pain.
