Chronic Pain Treatment With Opioid Analgesics

Benefits versus Harms of Long-term Therapy

Nalini Sehgal; James Colson; Howard S Smith


Expert Rev Neurother. 2013;13(11):1201-1220. 

In This Article

Opioids & Functional Outcomes

Clinical trials on opioids do not consistently report changes in functional status or health-related QoL (HRQoL) (Table 1, Table 2 & Table 3). Studies that report functional outcomes, differ in what is assessed and how is it assessed. The results from these trials are mixed and there is no conclusive evidence for improved physical, emotional or cognitive functioning in CNCP patients on long- term opioid therapy. Clinical trials that suggest opioids improve function, report improved scores on SF-12 for physical function,[39] or on Karnofsky Performance Status Scale,[65] or increase in general activity, walking,[66] climbing stairs,[38] mood, enjoyment of life[66] and sleep.[38,66] There are other studies which reveal that opioid therapy is associated with non-significant improvement in walking, general activity and normal work,[40] greater self-reported disability and poorer function,[67] lower scores in all subscales of SF-36, a significantly higher occurrence of depression and use of coping strategies as 'catastrophizing' and 'hoping and praying'.[68] Similarly systematic reviews of clinical trials show conflicting results, from no improvement in functional status[32] or inconclusive evidence[46] to increased function with opioids in CNCP.[48,49,61,69] In OA pain, function improved as compared to placebo, but the differences were small: 8.5% relative improvement in one review[69] and in another review 13% greater improvement (difference of 0.7 units between opioids and placebo on a 0–10 WOMAC scale).[48] Opioids did not improve depression scores,[61] but mood improved with significant pain relief.[61,66] A prospective study of primary care practices found significantly improved HRQoL scores in CNCP with low to moderate dose (20–40 mg/day morphine equivalent) opioid therapy compared to no opioid therapy or high dose therapy.[70] Short-term opioid use in older adults with CNCP reduced pain and improved physical function (sizes: -0.432; p <0.001) but resulted in poorer mental health function.[52] A cross-sectional population study from Denmark showed that opioid users had a lower mean score than non-opioid users on all eight subscales for HRQoL (SF-36).[71] Compared with non-opioid users, opioid users had greater odds for not being physically active in leisure time (odds ratio [OR]: 1.55), being unemployed (OR: 0.37), receiving disability pension (OR: 2.68).[71] In this study, 90% of opioid users also reported pain as moderate to very severe as compared to 46% non-opioid users with pain.[71]

Compared to a general clinical sample, patients with CP have poor baseline cognitive function,[72,73] particularly impaired concentration, attention and working memory deficits.[72,74,75] Poor performance on cognitive tests is associated with female sex, older age, lower education and income, depression, anxiety, tiredness and lower opioid dose.[76] Whether opioids improve or worsen cognitive function in CNCP is debatable, studies show contradictory results. Cognitive impairment is reported with opioid use[77,78] and the risk for CNS side effects (e.g., euphoria, cognitive impairment and sedation) increases in patients with cerebrovascular disease, dementia, brain injury or psychiatric illness.[79] It is not known if psychological health and pain severity are more predictive of decrease in cognition than opioid use. One study did not find cognitive function to be significantly different in CP patients on daily opioids versus intermittent opioids versus no opioids.[75] In another study CNCP patients on opioids were found to be no worse than those off-opioids on cognitive testing.[72] Some studies have suggested that opioids improve concentration, executive function,[80] psychomotor function[81] and scores on neurocognitive testing.[82] Yet other studies find that chronic opioid exposure is associated with impaired cognitive processing and psychomotor functions.[83–85] Opioid naïve subjects demonstrate impaired cognitive and psychomotor function after administration of a single dose of methadone or buprenorphine.[83] Chronic opioid exposure is associated with deficits across a range of neuropsychological domains with robust impairment in verbal working memory and cognitive impulsivity (risk taking) alongwith cognitive flexibility (verbal fluency).[85] Recent fMRI studies demonstrate alterations in neuronal activation in brain areas associated with working memory and addiction[86] and disruption in cerebro-cerebellar circuits in opioid dependent individuals.[87] Further research is needed to determine the clinical significance of impairments in cognitive and lab based tests for daily performance in the natural environment.

Psychomotor performance (attention, auditory and optical reaction times) is slightly impaired in patients on long-term opioid therapy, and becomes significantly more pronounced with increasing age, indicating a higher susceptibility of the elderly toward opioids.[77] A valid concern in this context then is the driving ability of CNCP patients on opioids. Driving is a complex task and requires integration of psychomotor function, visual-spatial abilities and cognitive skills.[88] Fishbain reviewed studies that assessed psychomotor function and driving ability in opioid dependent patients and found strong evidence for no impairment of psychomotor function and driving ability.[89] CP patients on stable doses of opioids are considered safe to drive provided certain criteria are met: an absence of co-prescriptions or other substances of abuse (alcohol or illicit drugs) with significant CNS effects, patients do not experience high levels of pain, an absence of a substantial sleep disorder or daytime somnolence and an absence of significant anxiety, depression or other psychiatric condition.[90] What is a stable opioid dose which is safe for driving is not known, and no study has compared driving performance and cognitive function in CP patients on opioids at low versus high doses. While patients on stable dose acquire a tolerance and may not demonstrate psychomotor impairment, an acute increase in opioid dose appears to cause psychomotor impairment to return.[91] Patients who have recently begun opioid therapy or who have recently increased their opioid dose are likely to demonstrate psychomotor impairment and may be at a greater risk for driving-related accidents.[20]

Overall, the evidence that long-term opioid therapy improves function and QoL in CNCP is mixed, some studies show improvement, some do not and some even show worse function. The assessment tools for measuring function differ among studies, some studies focus on specific functional goals, and not general function and no study has shown that opioids facilitate return to work. Cognitive function, manual dexterity and reaction times are maintained in patients on stable doses of opioids, so long other conditions that impair cognition and psychomotor function do not coexist.