Does opioid therapy improve the quality of life in patients with chronic pain? A systematic review and metaanalysis

Chronic pain is a worldwide major health issue in all modern societies. It affects the patient’s life in various dimensions of daily living and is associated with a significant loss of healthrelated quality of life (HRQL). Opioids are often used to treat chronic pain. As potent analgesics, they have become indispensable in pain therapy, but have also the potential of severe side effects. This systematic review with meta-analysis aims to answer the clinically important question if opioid therapy improves the HRQL in patients with chronic non-malignant pain. For this purpose, the databases PubMed (MEDLINE, PubMed Central), EMBASE and The Cochrane Library were searched in June 2020. Studies were included if they were doubleblind, randomized trials (RCTs), which compared opioid therapy to placebo for chronic pain and assessed a valid generic HRQL questionnaire. Studies investigating intrathecal or invasive opioid administration and fixed combinations of opioid and naloxone were excluded. Information on study population, study design, intervention, HRQL assessment and adverse events were extracted. The review is divided into two parts. A first qualitative part consists of a vote-counting approach, which assesses the direction of effects on HRQL, without considering effect size or significance. The second part is a meta-analysis of the results of the HRQL questionnaires SF-36, EQ-5D and the BPI pain interference scale. Also, the risk for premature study withdrawal was statistically analyzed. Altogether 2186 articles were screened and finally 35 RCTs, consisting of 11057 patient datasets were included in this review. In the qualitative analysis of the physical sum score PCS of the SF-36 questionnaire 22 out of 26 studies showed a positive effect favoring the opioid therapy. Also, the majority of studies which assessed the EQ-5D or the BPI showed a positive direction of effect. The statistical meta-analysis of the PCS, consisting of 7391 patient records, showed a mean difference of 1.82 [confidence interval: 1.32, 2.32] favoring opioid over placebo. Also the analysis of the EQ-5D, with data of 3634 patients, showed a significant advantage of 0.06 [0.00, 0.12] in favor of opioid therapy. A sensitivity analysis proved the stability of the significant effect in the PCS, whereas the effect in the EQ-5D becomes insignificant. The qualitative analysis of the mental summary scale MCS of the SF-36 showed an almost equal number of studies with a positive and a negative direction of effect. The meta-analysis on data of 7237 patients showed no significant differences (0.65 [-0.43, 1.73]) in the MCS. In the sensitivity analysis, the effect changes its sign to a negative direction. Due to an average high risk of bias, the overall evidence of the studies included is of low to medium quality. Especially remarkable is a high premature dropout rate of around 40% of the participants. Adverse events were reported as the most common reason for a premature study withdrawal during opioid therapy. In contrast to the mental dimensions of HRQL, which showed no significant effect of opioid therapy, the physical dimensions of HRQL demonstrated a statistically significant advantage over placebo. However, a clinical significance of this effect, which refers to individual clinical benefit for the patients, could not be demonstrated. As the mean study duration was about 9.3 weeks, the results of this analysis are valid for the first weeks and months of therapy. Further research on the long-time effect on HRQL in non-malignant pain may be necessary. Furthermore, this review shows that the dropout rate and, thus, the therapeutic adherence are significantly limited by the side effects associated with opioid intake. Further research may increase the tolerability of opioid therapy in order to enhance the efficacy in the therapy of chronic pain.