Analgesics

Suzanne Amato Nesbit and Julie Waldfogel

Introduction

Chronic pain affects about 100 million adults in the United States—more than those affected by heart disease, cancer, and diabetes combined.¹ The consequences of uncontrolled pain are broad including negatively impacting health, functional status, well-being, and quality of life. Obesity correlates highly with certain chronic pain conditions including osteoarthritis and fibromyalgia. The mechanisms behind this are not well described but may be related to increased mechanical stress as well as induction of chronic inflammatory states.² As the prevalence of obesity increases, the need to dose analgesics in obese patients will become more prevalent. In this chapter, we will review the data and discuss dosing of several different classes of analgesics in obesity including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), adjuvants, and opioids.

Acetaminophen

Acetaminophen is an analgesic and antipyretic discovered in the late 1800s. Despite over a century of use in medicine, its mechanism of action as an analgesic is still not completely understood. Acetaminophen is widely distributed through most body tissues except fat with an estimated volume of distribution (V_d) of 0.7 to 1.1 L/kg. It is approximately 10% to 25% protein bound.^3,4 Acetaminophen’s metabolism is of particular clinical interest. It is approximately 90% metabolized via saturable glucuronidation and sulfation pathways. Less than 5% is excreted unchanged in the urine.⁴ The remaining 5% to 10% is metabolized via cytochrome P450 (CYP) 2E1 to an active metabolite, N-acetyl-p-benzoquinone imine (NAPQI). In normal metabolism, NAPQI then conjugates with glutathione (GSH) to form an inert metabolite before excretion. In overdose, glucuronidation and sulfation pathways become saturated, forcing acetaminophen to metabolism via CYP2E1.³ The increased formation of NAPQI eventually depletes the body’s GSH stores, and the remaining NAPQI accumulates in hepatocytes and leads to acute liver failure (ALF).

With acetaminophen in many over-the-counter (OTC) analgesic products as well as in several prescription combination products, the risk for exceeding the daily maximum dose of acetaminophen is high. As a result, unintentional or intentional misuse of acetaminophen is the leading cause of ALF in the United States.⁵ Interestingly, data evaluating the effect of obesity on acetaminophen focus both on general pharmacokinetics (PK) and obesity’s potential effect on induced hepatotoxicity.

Pharmacokinetic Models

Two animal studies have evaluated the PK of acetaminophen in overfed rat models. In the first study, obese and control animals were dosed with 136.5 mg of acetaminophen intravenously (IV) as a flat dose.⁶ Data showed reduced concentrations of sulfate metabolites in obese rats as well as lower overall acetaminophen concentrations. Interestingly, clearance of acetaminophen was 27% higher in obese animals compared to controls, suggesting an alteration of elimination via increased drug metabolism. When adjusted for total body weight (TBW), the difference in clearance normalized, indicating increases in metabolic rate were roughly proportional to increases in body size.

The second study also used an overfed rat model.⁷ In this study, animals were administered one dose of acetaminophen 287 mg/kg based on TBW. Some results were similar to the first study. Sulfate metabolism was significantly reduced to approximately 41% of lean controls, and this seemed to be compensated by a resultant increase in glucuronide metabolism. However, this balanced overall to no change in total body clearance, which differs from the increased metabolism found in the prior study. Plasma acetaminophen concentrations also differed between studies, with this study finding initial concentrations to be similar before developing significantly elevated concentrations in obese animals over the subsequent 8 hours of observation. The reason for differences between the studies is unclear, but it may be related to differences in dosing (flat dose versus weight-based).

In humans, three studies have evaluated acetaminophen PK in obesity.^8-10 No study identified differences in half-life between obese and control patients. Although most studies (both animal and human) identified no change in V_d, one human study suggested there was a partial, but not complete, distribution of acetaminophen into excess weight above ideal body weight (IBW) and suggested a correction factor of 0.44 times IBW for men and 0.31 times IBW for women.⁹ One study evaluated plasma concentrations and found obese patients had a lower area under the curve as maximum plasma concentrations were reached at a later time and were significantly lower.⁸

Two of the three studies reported increases in acetaminophen clearance in obese patients, which normalized when corrected for TBW, again indicating a proportional increase in clearance with increasing body weight.^9,10 One study compared this acetaminophen clearance to clearance of lorazepam and oxazepam, both of which are exclusively metabolized via glucuronide conjugation.¹⁰ Clearance of lorazepam, oxazepam, and acetaminophen were highly correlated, suggesting an increase in glucuronide conjugation capacity in obese subjects, mimicking animal models. Also, the study showing no difference in acetaminophen clearance was the smallest with a total of seven patients and also noted a large degree of variability in PK parameters within their obese subjects, perhaps affecting these results.⁸

Hepatotoxicity

Several animal studies have evaluated the role of obesity in acetaminophen toxicity and demonstrate conflicting results.^11-15 In some studies, obesity appears to be protective with smaller increases in liver enzymes and fewer signs of injury histologically compared to lean controls.^12,13 Reduced CYP2E1 expression may play a role, with one study demonstrating increases in CYP2E1 expression from baseline in both groups during overdose, although the obese mice had only 58% of the expression of lean mice.¹³ Obese mice also had higher stores of GSH compared to their lean counterparts, suggesting both a preferential induction of protective conjugation pathways combined with increased GSH stores to bind NAPQI and reduce toxicity.^12,13

Conversely, other studies have demonstrated increased risk in obese animals.^11,14 In one study with an overfed model, rats were given a dose of either 710 mg/kg of TBW or 955 mg/kg of free-fat body mass.¹¹ Obese rats had a five-fold increase in alanine transaminase and 16-fold increase in alkaline phosphatase compared to lean controls. Unfortunately, difficulties in study design led to incomplete drug recovery from urine, which did not allow for characterization of metabolism. In another study, mice were given a dose of either acetaminophen IV 300 mg/kg or 600 mg/kg of TBW.¹⁴ Control, nonobese, and nondiabetic mice evidenced no change in labs or histopathology with the smaller dose and mild hepatic injury at 600 mg/kg. Comparatively, obese diabetic mice were more susceptible to injury, with mild damage at a dose of 300 mg/kg and severe necrosis at 600 mg/kg. As both studies used weight-based dosing, it is possible that the greater organ damage could be related solely to this dosing strategy. Plasma concentrations and target organ exposure was likely greater in the obese animals as acetaminophen has been demonstrated to distribute poorly into body fat.

Some of these conflicting results could also be explained by differences in the animal models used. Hepatic CYP2E1 activity can vary significantly between different rodent models, as can basal levels of oxidative stress and lipid accumulation in the liver. One recent study has attempted to explain the factors that could affect acetaminophen hepatotoxicity.¹⁵ Two different mouse models were used—one with a higher propensity for fatty liver disease (ob/ob mice) and one with higher levels of basal CYP2E1 activity (db/db mice). After administration of acetaminophen intraperitoneally 500 mg/kg of TBW dose, db/db mice had significantly higher increases (two- to three-fold) in liver enzymes compared to ob/ob or wild type controls. Db/db mice also demonstrated higher levels of liver necrosis histologically than either of the other groups.

In humans, retrospective cohort studies suggest a protective effect of obesity on acetaminophen-induced hepatotoxicity. In a database review of the Acute Liver Failure Study Group (ALFSG)—a group of 24 academic centers enrolling patients with ALF—data showed 167 (29.1%) out of 573 patients in the database with a documented body mass index (BMI) were obese.¹⁶ Interestingly, obese patients had a significantly lower prevalence of acetaminophen-induced ALF compared to nonobese patients, suggesting that obese patients may be less susceptible to ALF from acetaminophen. Similarly, a retrospective cohort study of patients who received N-acetylcysteine (NAC) for acetaminophen toxicity trended to less hepatotoxicity in the obese group (27.5% versus 37.5%; p = 0.34) with no differences in alcohol concentrations, alcohol history, total NAC dose, or maximum or final acetaminophen concentrations between groups.¹⁷

Helpful Tips

•The wide range of OTC and prescription products containing acetaminophen can increase the risk for unintentional overdose. Proper education and counseling is essential.

Summary

•Conflicting data exist for both PK and hepatotoxicity.

•Data demonstrate increases in acetaminophen clearance with increasing body weight.

•The occurrence of acetaminophen-induced ALF depends on a variety of features in obese patients. Factors including increased glucuronidation and GSH stores as well as decreases in CYP2E1 activity can provide protection. However, obesity may confer increased risk for other concomitant causes of hepatic injury and nonalcoholic fatty liver disease, which may exacerbate risk for ALF when compounded by an acetaminophen overdose.¹⁸

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are an important analgesic class. They work primarily through competitive, reversible inhibition of cyclooxygenase (COX) enzymes, which in turn reduce prostaglandin (PG) synthesis. Major adverse effects associated with this drug class include gastrointestinal (GI) bleeds, renal dysfunction, and increased cardiovascular risk (particularly with the COX-2 selective agents).

Ibuprofen

There has been one study of ibuprofen dosing in the obese.¹⁹ Eleven obese volunteers (average weight 114 kg) and eleven normal weight volunteers (average weight 61 kg) were given a dose of ibuprofen 600 mg orally after an overnight fast. There was no difference in absorption or elimination half-life between groups. However, obese patients presented with a lower C_max (36.9 mcg/mL versus 47.7 mcg/mL), suggesting some increased distribution in obese patients. Absolute V_d

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