Secondary and research interventions Botulinum toxin type A Local intradermal injection of botulinum neurotoxin type A may be helpful in chronic focal painful neuropathies. However, it causes muscle paralysis which may impact quality of life. Cannabinoids Evidence for the use of Cannabis based medicines is limited, low-moderate quality evidence suggests a benefit in pain intensity, sleep quality and psychological distress. The use of Cannabis has to be weighed against the negative psychotomimetic effects that may impact quality of life. Therefore, cannabis is not recommended as a mainstream treatment but may have a place for treatment refractory cases. Neuromodulators Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes. Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions that they might benefit. Deep brain stimulation The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%). There is a significant complication rate, which increases over time. Motor cortex stimulations Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which is associated with noticeable tingling (paresthesia) at treatment levels, the only palpable effect is pain relief. Spinal cord stimulators implated spinal pumps Spinal cord stimulators use electrodes placed adjacent to but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal. NMDA antagonism The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (ketamine), weak activity (memantine) or unacceptable side effects (dextromethorpan). Intrathecal