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• Treatment of central pain is still a great challenge. |
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• First-line drugs for central pain include tricyclic antidepressants and selective serotonin-noradrenaline reuptake inhibitors. |
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• If there is no relief with pharmacotherapy, nonpharmacological and surgical approaches may be used. |
Guidelines for the management of central neuropathic pain are listed in Table 3.
Table 3. Guidelines for the Management of Central Neuropathic Pain
Pharmacotherapy |
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• First-line therapy: antidepressants • Second-line therapy: antiepileptics, mexiletine, and experimental drugs • Third-line therapy: opioids |
Nonpharmacological measures |
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• Physical therapy • Positive relaxation • Motor imagery techniques with mirror therapy • Transcutaneous electrical nerve stimulation • Transcranial magnetic stimulation |
Neurosurgery |
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• Spinal cord stimulation • Motor cortex stimulation • Deep-brain stimulation • Thalamotomy |
Novel cellular and molecular approaches in development |
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• Cell and tissue transplants for pain • Gene therapy |
Pharmacotherapy. Categories of first-line drugs for central pain include tricyclic antidepressants and selective serotonin-noradrenaline reuptake inhibitors. Opioids and anticonvulsants are also used. None of the available drugs can adequately control central neuropathic pain, which is often resistant to pharmacotherapy.
Amitriptyline. Tricyclic antidepressants remain the most effective drugs for treatment of central neuropathic pain. The efficacy of this drug in poststroke pain has been established in controlled clinical trials. Amitriptyline does not act by its antidepressant effect, but rather as a noradrenaline reuptake inhibitor. The usual starting dose of amitriptyline is 10 to 25 mg at night for a few days, and then increased to 25 to 50 mg. After a week, the dose can be increased to 50 or 75 mg, depending on the toleration by the patient. Effective pain relief may not occur for several weeks.
Selective serotonin reuptake inhibitors are less effective than tricyclic antidepressants due to their high selectivity. Venlafaxine is the most promising of this category of drugs because it has a better side-effects profile than amitriptyline, but further investigation is required to establish its role in management of neuropathic pain.
Opioids. Morphine and methadone have limited efficacy in treatment of central neuropathic pain. A systematic review of controlled clinical trials showed only very low quality evidence that oxycodone is of value in the treatment of painful diabetic neuropathy or postherpetic neuralgia (17). Supraspinal central neuropathic pain may respond less well to a trial of opioids than spinal central neuropathic pain. Titrating to higher doses of potent opioids may be considered before they are judged to be unsuccessful for refractory supraspinal central neuropathic pain (49).
Anticonvulsants. Various anticonvulsants have been used extensively in the treatment of central pain. These include carbamazepine, valproic acid, and gabapentin. Lamotrigine is included in the list of anticonvulsants approved for the treatment of central neuropathic pain, but a randomized, double-blind, placebo-controlled trial did not support the use of lamotrigine in patients with multiple sclerosis.
Second-line treatment involves the use of several agents, including the following:
Mexiletine. Mexiletine has been shown to be effective in poststroke central pain. It can be used to replace amitriptyline therapy (if ineffective) or can even be combined with it. If used as an outpatient treatment, a small starting dose of 50 mg twice daily is recommended, with weekly increments of 50 to 100 mg. Beneficial effect is usually seen at a dose of 400 to 600 mg/day. Patients need to be monitored, and electrocardiographic examinations are mandatory. One third of the patients discontinue therapy due to severe nausea and vomiting. Hypotension is another adverse reaction. Hospitalization is recommended if treatment is to be started with higher loading doses.
Third-line treatment involves the use of several agents, including the following:
Intravenous local anesthetics. Intravenous ketamine, a noncompetitive NMDA receptor antagonist, is primarily used for the induction and maintenance of general anesthesia, but it has also been used for the management of central neuropathic pain. Randomized controlled trials have shown that intravenous lidocaine relieves central pain. A possible mechanism of pain relief following ketamine treatment is regression of the NMDA receptor to resting state, which inhibits the propagation of nociceptive signals to the brain. A patient with Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in intractable central pain syndrome responded to a 1-week course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, resulting in marked reduction in the use of analgesics including opioids (36). The evidence for efficacy of ketamine is moderate but in situations in which standard analgesic therapies have failed ketamine is a reasonable option. One drawback is that ketamine cannot be repeated too often because of its adverse effects.
Transdermal buprenorphine. Results of treatment of central neuropathic pain syndromes with buprenorphine are encouraging (21).
Transdermal capsaicin. Neuropathic pain after spinal cord injury is often refractory to standard treatments. Capsaicin 8% transdermal patch, an FDA-approved treatment of neuropathic pain in postherpetic neuralgia, has been shown to be effective for neuropathic pain in spinal cord injury in off-label use (55).
Clinical trials of treatments for central neuropathic pain. As of February 26, 2021, 97 clinical trials for “central neuropathic pain” are listed on ClinicalTrials.gov. Some of the publications relevant to these trials include the following:
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• Cannabinoids. A randomized, controlled, double-blind, crossover pilot study showed that dronabinol, a cannabinoid, was no more effective than diphenhydramine for relieving chronic neuropathic pain after spinal cord injury (48). Results of a phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol/cannabidiol oromucosal spray to relieve central neuropathic pain in multiple sclerosis showed conflicting results in the 2 phases of the study indicating that further studies are required to evaluate the role of cannabinoids in the management of this type of pain (33). A systematic review of randomized, double-blind controlled trials of cannabis-based medicine found that any relief of central neuropathic pain may be outweighed by their adverse effects (40). |
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• Results of a randomized, double-blind, placebo-controlled trial showed that a single subcutaneous injection of botulinum toxin type A significantly reduced intractable chronic neuropathic pain in patients with spinal cord injury (23). |
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• A randomized clinical trial is evaluating neurofeedback therapy for central neuropathic pain in spinal cord injury (NCT02178917). It is based on an open study, which showed that neurofeedback treatment resulted in reduced central neuropathic pain and a widespread reduction of cortical activity during imagination of movement (26). Characteristic EEG “signatures” that are probably related to central neuropathic pain have been defined and are the basis of neurofeedback, as these were shown to patients on a computer screen in a simple graphical form. Patients were trained to change their brain activity at will and, as a result, their pain was reduced. The trial is ongoing and interim results have not been published. |
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• A systematic review of randomized controlled trials that evaluated therapies for central poststroke pain, including anticonvulsants, an antidepressant, an opioid antagonist, repetitive transcranial magnetic stimulation, and acupuncture therapies, concluded that there was little or no effect on pain or other patient-important outcomes (41). |
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• A randomized, double-blind, sham-controlled, 3-arm parallel study has compared the analgesic effects of stimulation of the anterior cingulate cortex or the posterior superior insula against sham deep repetitive transcranial magnetic stimulation in patients with central neuropathic pain after stroke or spinal cord injury (NCT01932905). Pain relief with anterior cingulate cortex or the posterior superior insula was not different from sham stimulation despite a significant antinociceptive effect after insular stimulation indicating that pain can be modulated by directly stimulating deeper cortical structures without necessarily affecting clinical relief (16). |
Nonpharmacological measures. Positive relaxation (ie, by group therapy or use of audio tape) can be a useful adjunct to pharmacotherapy. Cognitive behavioral therapy has also been tried. Transcutaneous electrical nerve stimulation as an adjuvant therapy has been shown to be helpful in some cases. Acupuncture has also been used for relief of central pain, particularly following spinal cord injury (58). A Cochrane Database review of randomized controlled trials found insufficient evidence for the efficacy of nonpharmacological interventions for chronic neuropathic pain due to spinal cord injury (06).
Neurosurgical approaches. A historical review of neurosurgical attempts to control central pain describes several procedures that have been tried and abandoned (59). The first procedure to be performed for central pain, spinothalamic cordotomy, is no longer used because central neuropathic pain at the spinal level is a complication of this procedure. Resection of sensory cerebral cortex for thalamic pain has little to recommend from a physiological point of view because pain is interpreted at the thalamic level. There are reports of some relief of pain by frontal lobotomy, but resulting personality alterations and undesirable psychic changes now rule out this option. Stereotactic mesencephalotomy has been abandoned because of recurrence of pain in two thirds of patients after 6 months, along with the occurrence of dysesthesias as a postoperative complication. Neurosurgery is considered a treatment of last resort for chronic pain resistant to all other therapeutic measures. Procedures that are still performed for central pain include the following:
Spinal cord stimulation. Spinal cord stimulation involves the electrical stimulation of dorsal structures within the spinal cord and has been used frequently for the relief of chronic pain. It is often used for nonneuropathic pain such as that of angina pectoris. This procedure has been used successfully for relief of severe neuropathic pain in both lower limbs secondary to idiopathic acute transverse myelitis that had failed to respond to conventional pain therapies. Based on current evidence, spinal cord stimulation may represent a valuable treatment option, particularly for patients with chronic pain of predominantly neuropathic origin and topographical distribution involving the extremities. An open study has shown that spinal cord stimulation provides improved pain control in patients with intractable central poststroke pain (03).
An implantable neurostimulation system for dual channel therapy is designed to aid in the management of chronic intractable pain of the trunk or limbs. It has been shown to be effective in controlling neuropathic pain at the spinal level. The device has been approved for distribution by the United States Food and Drug Administration.
Motor cortex stimulation. Motor cortex stimulation is carried out by surgically implanted epidural electrodes for chronic motor cortex stimulation. Functional MRI is a useful guide for the operative targeting of selective motor cortex areas in neuropathic pain. Motor cortex stimulation has not been universally accepted because of controversy about the indications and variations in the efficacy reported in different series of cases. A study has reported that burst mode of motor cortex stimulation is more effective than tonic mode and should be considered when tonic stimulation is not sufficient in refractory neuropathic pain (50).
Deep-brain stimulation. Deep-brain stimulation is usually carried out after implantation of electrodes in medial and lateral ventroposterior thalamic nuclei and periaqueductal gray matter. In a series, good results were obtained with relief. Deep-brain stimulation has not provided satisfactory relief of thalamic pain and post spinal cord injury patients. Deep-brain stimulation is used more often in patients with Parkinson disease rather than for treatment of central pain. In a patient with central poststroke pain, permanent electrode placement following initial pain relief by stimulation of periventricular gray region and nucleus accumbens led to sustained relief reported at 1 year of follow-up (37). A long-term efficacy study of deep brain stimulation showed that benefit and efficacy varied by etiology, with relief in 70% of the cases with post-stroke pain (05). Review of the literature and long-term follow-up of a small series of patients suggests that stimulation of the posterior limb of the internal capsule is safer and more effective than motor cortex stimulation in treating patients with chronic neuropathic pain affecting the lower limb as it is a more targeted treatment for the subset of patients whose pain and spasticity are referred to the lower limbs (14). Deep brain stimulation to treat neuropathic pain refractory to pharmacotherapy has regulatory approval in the United Kingdom, but not in the United States.
Stereotactic thalamotomy. Stereotactic thalamotomy is performed predominantly for movement disorders and rarely for pain. For neuropathic or deafferentation pain, the preferred target is usually the sensory nucleus of the thalamus at a site corresponding somatotopically to the location of the pain. Thalamotomy of the principal sensory nucleus and its rostral part has been shown to ameliorate central poststroke pain.
Noninvasive brain stimulation. Techniques for noninvasive brain stimulation include transcranial direct-current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS). Application of rTMS over the motor cortex has been claimed to produce short-term relief of some types of central neuropathic pain. An open study of combination of rTMS over the motor cortex with motor imagery exercises and mirror therapy reported a significant decrease in pain at 48 hours, which was a good indicator of long-term response to this treatment (34).
Transcranial direct-current stimulation involves the application of a weak electric current to the cerebral cortex through the scalp, modifying neuron membrane excitability, which may lead to neuroplasticity following daily sessions. Use of tDCS for central pain is controversial. Results of a sham-controlled randomized clinical trial on patients with chronic neuropathic pain due to human T-lymphotropic virus type 1 infection showed no significant relief (51). A systematic review of the literature, including clinical trials, indicated significant effects of tDCS on central neuropathic pain as compared to the control group, but no definite conclusions about the efficacy of the neuromodulating effect of tDCS due to inconsistencies in methods and diversity of results obtained (09).
Noninvasive cortical stimulation is limited by the limited duration of the analgesic effects and the need to perform the procedure in hospital settings. A study has proved that internet-based, long-duration tDCS at home is safe and technically feasible for providing long-lasting relief in 50% of patients with central neuropathic pain (15).
A consensus by Latin American and Caribbean experts, based on a systematic review of the literature, recommends noninvasive central nervous system neuromodulation by tDCS and rTMS for the control of central neuropathic pain, as it has no severe adverse reactions, even though the analgesic effects are low to moderate (04).
Novel cellular and molecular approaches in development. Several cell and tissue transplant as well as gene therapy procedures are in development for chronic pain, but none of these are suitable for application in central pain. The implants secrete analgesic substances and are refined methods of drug delivery.
Cell therapy. Chronic delivery of antinociceptive molecules by means of cell grafts near the pain processing centers of the spinal cord has been investigated for the treatment of central neuropathic pain (30). Based on animal experimental studies, neural stem cell transplantation is a potential option for relieving neuropathic pain after spinal cord injury by reducing overexpression of P2X receptors (11).
Gene therapy. Gene therapy approaches include the use of viral vectors for delivery of genes for analgesic peptides. Although no specific gene therapeutic approach for central pain exists, analgesic therapy may be provided in a manner adequate to control pain. Viral vector-mediated gene transfer to dorsal root ganglia could be employed to treat central neuropathic pain after incomplete spinal cord injury (29). Reduction of neuropathic pain by intrathecal administration of an antiinflammatory interleukin-10 nonviral gene therapy formulation (XT-101-R) in a rat model of relapsing remitting experimental autoimmune encephalomyelitis supports gene therapy as a clinical strategy for the treatment of neuropathic pain associated with multiple sclerosis (18). Intrathecal injection of AAV vectors encoding combined serine histogranin (NMDA antagonist) and endomorphin1 (opioid) constructs into animal models of spinal cord injury can provide long term attenuation of neuropathic pain without significant adverse effects and has a clinical potential (31).