Obesity rates have increased substantially in recent years, with an estimated prevalence in 2013 and 2014 of 37.9% among Americans over age 20 years, according to the Centers for Disease Control and Prevention.1 Previous findings have linked excessive weight and obesity with a reduction in life expectancy comparable with that observed among cigarette smokers, in addition to increased morbidity and healthcare costs.2
A major challenge in treating patients who are obese is their altered pharmacokinetic profile, which can accompany physiologic changes in this population.3 “Derangements in cardiovascular and respiratory physiology make patients with morbid obesity more vulnerable to drug-induced respiratory depression and upper airway obstruction, thus increasing the risk of treating them with opioids,” wrote the authors of a recent review article.4
“While acute pain management is complex at baseline, it is particularly complicated by the unique risks of the obese patient,” review co-author Halena M. Gazelka, MD, assistant professor of Anesthesiology and Perioperative Medicine at the Mayo Clinic, told Clinical Pain Advisor. Despite these risks, there are a dearth of published data regarding acute pain management in people who are obese, especially in individuals with “super obesity” (ie, body mass index (BMI) >50 kg/m2 or weight that exceeds ideal weight by >150 pounds).
The authors of the review also described a case study highlighting the challenges in determining optimal approaches to pain management for this patient population in light of limited evidence or guidance. The authors also discussed altered pharmacokinetics in 3 critical physiologic parameters in obese individuals, as summarized below.
Volume of distribution (Vd). Because of its affinity for adipose tissue, the Vd of highly lipophilic drugs is significantly increased in obese vs non-obese patients, but the Vd of hydrophilic drugs is similar between the two groups. Thus, the loading dose of highly lipophilic drugs should be based on the patient’s total body weight, and the loading dose of hydrophilic drugs should be based on the patient’s ideal weight.
“Wide variation in the impact of Vd remains, since each drug’s affinity for excess adipose tissue is unique. For example, remifentanil is highly lipophilic but shows minimal to no change in Vd in individuals who are obese,” note the authors of a study investigating the pharmacokinetics of the drug.5 Other factors that influence Vd include plasma protein binding, tissue blood flow, and cardiac performance.
Drug clearance. Hepatic and renal physiology, and thus drug clearance, may be altered in patients with obesity. “[Drug clearance] is inversely related to the steady-state plasma concentration and is the primary determinant when calculating maintenance dosage,” state the authors. Obese individuals were found to have increased cytochrome P450 2D6 (CYP2D6) activity, whereas cytochrome P450 3A4 (CY3A4) activity does not appear to be related to body weight.6 “Therefore, drugs metabolized via CYP3A4 (eg, fentanyl, alprazolam, midazolam, oxycodone [partially]) should be used with caution given the reduced metabolism exhibited by patients with extreme obesity,” advised the authors.5,7
Elimination half-life. As the half-life of a drug depends on the Vd and drug clearance, increased Vd or reduced drug clearance may extend half-life, and chronic use of certain drugs could lead to accumulation in adipose tissue, which has associated risks. “Medications like fentanyl, propofol, and methadone would also be expected to have an extended elimination half-life,” the authors stated. “Subsequent doses of lipophilic drugs should be dosed cautiously.”
Dr Gazelka spoke further with Clinical Pain Advisor about treatment implications for people who are obese and next steps in this area.
Clinical Pain Advisor: What are the top clinical implications for patients who are obese?
Dr Gazelka: Caution must be exercised when treating the morbidly obese patient with pain medications — even more caution than the “standard of care,” given the risks for sleep apnea-associated respiratory depression, poor medication clearance (increased fat stores of commonly utilized pain medications), and the tendency to use “weight-based” dosing.
Further, morbidly obese patients may be at risk for undertreatment of pain. We tend to use “common dosing” to manage pain, and while the morbidly obese are at higher risk for morbidity [associated with] pain management, they also may require larger doses — but clear them more slowly. They require close observation and management by those familiar with both the medications and the unique needs of this population.
Clinical Pain Advisor: What should next steps in this area be in terms of research?
Dr Gazelka: As this population is increasing, we need to understand the pharmacodynamics and pharmacokinetics of these medications as they apply to the morbidly obese. Most studies on these topics are not only older, they were also performed on “ideal weight” subjects — and may not be broadly applicable to those of higher BMI.
Questions to be explored include: What are the true risks for pain management in the very obese population? Should we be managing these patients differently — with different parameters for monitoring, for instance — than other patients? Are there alternatives to commonly used medications (eg, opioids, benzodiazepines, sedatives) that we should be exploring to manage pain for both the morbidly obese and the general population — for example, complementary and alternative techniques to enhance pain management, minimize opioid risk, and reduce side effects?
Our contact with morbidly and super obese patients is only going to increase in coming decades if the current trajectory in the population is an indicator, and it would behoove all providers engaged in pain management — and will benefit our patients — if we learn and understand what we can about the unique needs, concerns, and risks for this population.
- Centers for Disease Control and Prevention. Obesity and Overweight. https://www.cdc.gov/nchs/fastats/obesity-overweight.htm. Updated May 3, 2017. Accessed January 4, 2018.
- Peeters A, Barendregt JJ, Willekens F, et al. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003;138:24-32.
- Cheymol G. Effects of obesity on pharmacokinetics: implications for drug therapy. Clin Pharmacokinet. 2000;39:215-231.
- Kramer NM, Gazelka HM, Thompson VH, Batsis JA, Swetz KM. Challenges to safe and effective pain management in patients with super obesity: case report and literature review [published online November 15, 2017]. J Pain Symptom Manage. doi: 10.1016/j.jpainsymman.2017.11.005
- Egan TD, Huizinga B, Gupta SK, et al. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology. 1998;89(3):562-573.
- Ghobadi C, Johnson TN, Aarabi M, et al. Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: expected variations in clearance. Clin Pharmacokinet. 2011;50(12):809-822.
- Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet. 2010;49(2):71-87.