Risks Associated with Chronic Opioid Therapy

Medication Misuse and Addiction
Since 1990, the misuse of prescription opioids has increased dramatically worldwide.³² Though the actual risk of developing opioid addiction is unknown, it is considered small, but certainly not zero. Rates of substance use disorders are increased in long-term prescription opioid users compared to those who do not use opioids.³³,³⁴ This risk increases in the presence of psychiatric disorders such as depression and anxiety.³⁵ A recent review estimated that for patients, who are treated with opioids for chronic pain, the risk of developing addiction or abuse ranges from approximately 3%-12%.³⁶ In the event that chronic opioid therapy needs to be discontinued, patients must be gradually tapered off. Not every patient will be able to successfully complete this aspect of their care. Patients at risk for drop-out, and subsequent relapse into the use of opioids, have higher ratings of pain intensity and depressive symptoms.³⁷ The prescriber should screen for, and more aggressively treat, both pain and depression with appropriate non-opioid therapies before detoxification to increase the likelihood for successful discontinuation.

Death
Prescription opioid-related deaths by overdose have increased significantly over recent years. The availability of prescription opioids is a requirement for abuse and overdose but specific aspects of prescribing practices (eg, short- vs long-acting opioids, type of opioid, dose, schedule, and patient population) may define the highest risk conditions. In a case-cohort study of 1) 750 unintentional prescription opioid overdose deaths and 2) a random sample of patients receiving opioid therapy for pain, the risk of overdose death was directly related to the maximum prescribed daily dose of opioid medication.³⁸ In different populations of patients taking more than 100 mg per day compared to those taking less than 20 mg per day, adjusted hazard ratios ranged from 4.5 (substance use disorders) to 7.2 (chronic pain). Another study of opioid overdose found that the risk of death increased by almost 9 times when patients were receiving 100 mg per day or more compared to those patients receiving 20 mg per day or less.³⁹ The same group of investigators showed that doses greater than or equal to 50 mg per day doubled the risk of fractures among older adults prescribed opioids for chronic non-cancer pain.⁴⁰

Dosing Titration and Tolerance
Interestingly, how patients reach high total daily doses of opioids may be an artifact of the existing guidelines for chronic opioid therapy. Time-scheduled opioid dosing in contrast to pain-contingent dosing is expected to stabilize opioid serum levels, improve pain relief, minimize side effects, decrease reinforcement of pain behaviors, and lower risk of addiction by decreasing exposure to both the effects of opioid onset (euphoria, pain relief) and termination (increased pain, end-of-dose withdrawal symptoms) of action. In a survey of almost 1800 patients receiving chronic opioid therapy for chronic non-cancer pain, time-scheduled dosing resulted in a significantly higher average daily opioid dose than pain-contingent dosing (97 mg vs 32 mg morphine equivalents). Additionally, using the Prescribed Opioids Difficulties Scale, more patients in the time-scheduled dosing group expressed concern about opioid level control.⁴¹

Another concern about chronic opioid therapy and opioid dosing is the risk of developing tolerance, which can result in seemingly endless escalation of the total daily amount of opioid prescribed. In a chart review study of almost 200 patients treated by a pain specialist, the average daily dose of opioid was 180 mg morphine equivalents.⁴²  More important with respect to tolerance was how dosing changed over an average treatment period of 57 months. Approximately 35% of patients remained on stable doses after initial titration; 13% had stabilization of dosing within 1 dose change; and 15% decreased their dose after surgeries or interventional procedures. These findings suggest that the majority of patients do not experience tolerance-necessitating dosage increases.  A more controversial outcome of long-term, high-dose opioid therapy is opioid-induced hyperalgesia.⁴³  Paradoxically, increases in pain related to treatment with opioids could result in even higher doses of opioids being prescribed.⁴⁴  The clinical observation that pain can actually improve with the discontinuation of opioid therapy should lend support to consideration that opioids may be providing more harm than benefit.  This stresses the importance of monitoring.