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 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.