Death after initiation of intrathecal drug therapy for chronic pain: assessing risk and designing prevention.

THE use of intrathecal drug delivery has emerged as a viable option for the long-term treatment of cancerrelated pain, and significant evidence has emerged to bolster its place in our pain treatment armamentarium. Use of this therapy has grown dramatically for chronic noncancer pain, particularly for the treatment of chronic back pain. The evidence to support efficacy in this realm is growing, but it remains inadequate; patient selection remains empiric, and efficacy and long-term safety have yet to be established. At the same time, the complications associated with this long-term therapy have grown more evident, particularly the appearance of neurologic injury associated with catheter-tip granuloma formation. It is now clear that many of the actual drug combinations and concentrations in clinical use had not been adequately tested in preclinical models. In this issue of ANESTHESIOLOGY, the manufacturer of the most common device used to provide intrathecal therapy details a series of deaths reported within 1 day of implant in February 2006. The manufacturer has teamed with a group of experts and has used large databases to understand if this therapy is indeed associated with excess mortality. They conclude that patients with noncancer pain treated with intrathecal opioid therapy experience increased mortality compared to similar patients treated by using other therapies. This is a striking conclusion, and many questions arise. Is this excess mortality real or an artifact of the methodology used? What can we learn from the analysis to improve the safety of intrathecal drug therapy? Are there improvements in the technology associated with this device that could be applied to improve its safety? Is this excess mortality real or an artifact of an imperfect analysis? One of the strengths of the study data set is that the large, stable study population affords a look at a variety of concomitant medications and important subgroups. Adequate sample size allowed the authors to restrict their exposure groups to new initiators of the opioid delivery devices and to control for several potential confounders using what amounts to an incident user cohort design. An incident user design reduces the likelihood of missing early adverse events, allows for an evaluation of risks over time, ensures that the assessment of patient baseline characteristics is uninfluenced by any effects of exposure/treatment, and reduces the likelihood that treatment assignment is influenced by past experience. To have unadulterated exposure groups, the authors compared monotherapies with each other and censored patient follow-up as soon as the patient switched devices or augmented therapy with other devices. This analytic strategy makes treatment groups comparable with regard to initial health state and avoids comparing patients who change treatment groups in response to treatment failure or side effects to those who do not. In addition, automated pharmacy records are a good source of medication data because these records are not subject to information bias. Residual misclassification is conservative, mitigating against bias that would favor detecting a drug effect. Despite the strengths in the study design, the study may resist generality beyond patients receiving intrathecal opioid versus spinal cord stimulation as monotherapy, a limitation that affects generality to a large proportion of patients because many patients who receive treatment with spinal cord stimulation are also receiving a range of other treatments concomitantly. The current study has limited ability to adjust for confounders such as severity of illness and circumstances surrounding the events (deaths). The authors attend to these critical issues by conducting several sensitivity analyses with other data sets, and they make a compelling argument for consistency of gross effects, but results may not be applicable to other groups of patients, e.g., younger ones. The authors might have considered sensitivity analyses that examine residual confounding using propensity score calibration and instrumental variable techniques, which allow more efficient matching than standard regression procedures when examining a rare outcome. So, the conclusion that initiation of treatment with intrathecal opioid therapy results in excess mortality appears to be sound. Where might these risks arise, and how can we alter our practice to minimize risk? Unfortunately, the large database analyses do not answer these questions, and we must turn to clinical experience and the scant information that can be gleaned from the index cases in the current report. The use of intrathecal drug therapy is technically challenging and relies on an understanding of the pharmacology of intrathecal opioids and proper use of the infusion device. The role of the individual practitioner is critical in assuring safe initiaThis Editorial View accompanies the following article: Coffey RJ, Owens ML, Broste SK, Dubois MY, Ferrante FM, Schultz DM, Stearns LJ, Turner MS: Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. ANESTHESIOLOGY 2009; 111:881–91.