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Intrathecal Drug Delivery for Neuropathic Pain •


area, severe cognitive impairment); and positive response to an intrathecal trial.


Given that delivery of medications into the subarachnoid space carries risks beyond those associated with the actual medications, the decision to proceed with this therapy must be carefully undertaken. Procedural risks range from the mild, such as post-dural puncture headache, to the potentially catastrophic, such as neuraxial infection or hematoma. Adverse effects attributable to the medications are class-dependent but can be severe, including respiratory depression, seizures, weakness, hallucination, or suicidal ideation. The risks of both the procedure and medication(s) to be delivered must be considered and balanced against the risks of a patient’s current therapy and untreated pain.


Selection criteria are intended to identify patients who have failed more conservative therapy and do not have contraindications to intrathecal therapy. In contrast to cancer pain, intrathecal treatment for neuropathic pain poses additional challenges given the variety of etiologies. The primary methods of performing an intrathecal trial are single-shot subarachnoid injection or longer-term trial infusions into either the epidural or subarachnoid space. The trial period is crucial in establishing the efficacy of the proposed therapy and in determining whether adverse effects will be of such prominence as to render the therapy unfeasible. However, an inherent shortcoming is that the development of some adverse effects in the long term may not be predicted by the success of a short-term trial (i.e. tolerance, edema, and hyperalgesia with opioid therapy). Despite the potential risks of intrathecal therapy, in the proper setting it can play an important role in the amelioration of refractory neuropathic pain.


Opioids


The discovery of opioid receptors in the central nervous system was reported in several studies in 1973.5–7


This discovery led to experimentation


with intrathecal morphine in animals and, ultimately, the first reported use of intrathecal opioids by Wang and colleagues in 1979.8,9


Following


the success noted in Wang’s study (all eight patients with refractory cancer-related pain noted resolution of pain with intrathecal morphine), the use of intrathecal opioids in treating a variety of pain conditions has blossomed.


Found in high concentrations in the dorsal horns of the spinal cord, opioid receptors are broadly classified into several subtypes to include mu, delta, and kappa.10


The mu receptor is the most clinically relevant as it mediates the analgesic effects of commonly used agonists such as morphine, hydromorphone, and fentanyl. Pre-synaptic binding of opioid agonists leads to decreased release of pro-nociceptive neurotransmitters (substance P and calcitonin gene-related peptide), while post-synaptic binding yields increased threshold to action potential via neuronal hyperpolarization.11


The clinical effects of intrathecal opioids are dependent not only on their affinity for the opioid receptor but also on their movement and solubility within the cerebrospinal fluid. Among opioids suitable for intrathecal administration, morphine is the most hydrophilic, followed by hydromorphone. Higher levels of hydrophilicity allow greater and faster rostral spread within the cerebrospinal fluid and delay systemic spread. Conversely, the lipophilic characteristics of fentanyl and sufentanil result


US NEUROLOGY


in greater systemic absorption and decreased movement within the spinal column. These properties must be taken into account when selecting an agent, as lipophilic agents need to be delivered more proximally to the targeted area than their hydrophilic counterparts.12


The first clinical trial researching the effects of intrathecal opioids on chronic pain was published by Smith et al.13


in 2002. A total of 202 patients


with refractory cancer pain were randomized to receive either intrathecal opioids via an implantable drug delivery system (IDDS) plus comprehensive medical management (CMM) or CMM alone. The majority of patients had mixed neuropathic pain (60 % in the CMM group, 61 % in the IDDS group), while an additional 14 % of the CMM group and 13 % of the IDDS group had strictly neuropathic pain. Fifty-one IDDS patients had intrathecal pumps placed within four weeks of their trial. Forty-eight patients had morphine added in their pumps while three received dilaudid; in addition, 15 had bupivacaine, two clonidine, and one droperidol added. At four-week follow-up, the results favored the IDDS group, who displayed an overall greater reduction in visual analog scale (52 versus 39 %) and greater reduction in toxicity-related adverse effects (50 versus 17 %). These results persisted at six-month follow-up. A slight trend was noted whereby the IDDS group displayed greater survival at six months (54 versus 37 %). Rauck and colleagues14


published a multicenter, prospective, open-label study investigating the effects of intrathecal morphine in cancer patients in 2003. Among the 124 enrolled patients with refractory cancer pain, 119 went on to have a successful trial and were implanted with an IDDS. The study did not detail the nature of the patients’ pain characteristics, although it is reasonable to assume there were high rates of neuropathic pain. A 31 % reduction in pain score at one month post-implantation was observed, which was maintained until the final follow-up at 16 months. The data also demonstrated a statistically significant decrease in systemic opioid-related adverse effects.


There are several large retrospective studies which have shown good effect for intrathecal opioids in malignant and non-malignant pain. A 1996 retrospective, multicenter study performed by Paice et al.15


collected


conducted a similar study in 1996 examining the results of 120 patients with primarily neuropathic pain. The results showed a mean pain reduction of 67 % six months following initiation of intrathecal opioid therapy and a mean reduction of 58 % at the longest follow-up of four years. Similar rates of pain relief and patient satisfaction have been attained in other retrospective studies of patients with neuropathic and mixed somatic–neuropathic pain conditions.17–19


Although randomized and prospective trials have not been performed to address the role of intrathecal opioids in strictly neuropathic pain conditions, the overall evidence is good given the high prevalence of


155


data on 429 patients receiving intrathecal opioids via an IDDS. The study consisted of a survey sent to physicians and patients for the purpose of collecting data on screening, outcomes, dosing, and adverse effects. Commensurate with prior and subsequent studies, there was a strong presence of neuropathic pain among the patient population (38 % with purely neuropathic pain, with an equal proportion suffering from mixed somatic and neuropathic pain). Overall, patients reported a mean pain reduction of 61 % following initiation of therapy. Two-thirds reported they were very satisfied with their pain relief, 20 % reported moderate satisfaction, and only 4 % reported being very dissatisfied. Winkelmüller and Winkelmüller16


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