User:Neurotip/Neuropathy/Neuropathic pain

The starting point for neuropathic pain is a lesion or dysfunction within the somatosensory system. Current knowledge regarding the mechanisms of neuropathic pain is incomplete and is biased by a focus on animal models of peripheral nerve injury.

Under normal circumstances, pain sensations are carried by unmyelinated and thinly myelinated nerve fibers, designated C-fibers and A-delta fibers respectively. After a peripheral nerve lesion, a neuroma may develop at the stump. The neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and elevated sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization".

The dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop an increased background activity, enlarged receptive field and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization has been proposed as an important mechanism of persistent neuropathic pain.

Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Nociceptive pain can be described as the one that can occur in our everyday life as an aftermath of a simple insult or injury. The mechanism for such type of pain can be generated by transduction, which converts the stimulus into electrical activity in specialized nociceptive primary afferent nerves.Guddin, J.A. Expanding Our Understanding of Central Sensitization. 'Medscape''1994-2008. [http://www.medscape.com/viewarticle/481798]. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”

Non-neural glial cells may play a role in central sensitization. Peripheral nerve injury induces glial to releasing glial proinflammatory cytokines and glutamate which, in turn influence neurons.{{cite journal |author=Wieseler-Frank J, Maier SF, Watkins LR |title=Central proinflammatory cytokines and pain enhancement |journal=Neuro-Signals |volume=14 |issue=4 |pages=166–74 |year=2005 |pmid=16215299 |doi=10.1159/000087655 |s2cid=3467891 |url=}}

The phenomenon described above are dependent on changes at light-microscopic and submicroscopic levels. Aberrant regeneration, altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play.{{cite journal |author=Truini A, Cruccu G |title=Pathophysiological mechanisms of neuropathic pain |journal=Neurol. Sci. |volume=27 Suppl 2 |issue= |pages=S179–82 |year=2006 |date=May 2006 |pmid=16688626 |doi=10.1007/s10072-006-0597-8 |s2cid=28736907 |url=}}

Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.{{cite journal |author=Dworkin RH, O'Connor AB, Backonja M, et al. |title=Pharmacologic management of neuropathic pain: evidence-based recommendations |journal=Pain |volume=132 |issue=3 |pages=237–51 |year=2007 |pmid=17920770 |doi=10.1016/j.pain.2007.08.033|s2cid=9333155 }}

In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy.{{cite journal |author=Attal N, Cruccu G, Haanpää M, et al. |title=EFNS guidelines on pharmacological treatment of neuropathic pain |journal=Eur. J. Neurol. |volume=13 |issue=11 |pages=1153–69 |year=2006 |pmid=17038030 |doi=10.1111/j.1468-1331.2006.01511.x|s2cid=15446990 }}{{cite journal |author=Moulin DE, Clark AJ, Gilron I, et al. |title=Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society |journal=Pain Res Manag |volume=12 |issue=1 |pages=13–21 |year=2007 |pmid=17372630 |doi=10.1155/2007/730785|pmc=2670721 |doi-access=free }} These have combined evidence from randomized controlled trials with expert opinion.

Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.

It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.

Favored treatments are certain antidepressants e.g. tricyclics and selective serotonin-norepinephrine re-uptake inhibitors (SNRI's), anticonvulsants, especially pregabalin (Lyrica) and gabapentin (Neurontin), and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive receptors, or desensitize C fibers such that they transmit fewer signals.

Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.

{{main|Antidepressants}}

The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the brain. Antidepressants will relieve neuropathic pain in non-depressed persons.

In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.{{cite journal |author=Bennett G, Xie Y |title=A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man |journal=Pain |volume=33 |issue=1 |pages=87–107 |year=1988 |pmid=2837713 | doi = 10.1016/0304-3959(88)90209-6 |s2cid=22942169 }}{{cite journal |author=Seltzer Z, Dubner R, Shir Y |title=A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury |journal=Pain |year=1990 |volume=43|issue=2 |pages=205–218 |pmid=1982347 | doi = 10.1016/0304-3959(90)91074-S |s2cid=10540235 }}{{cite journal |author=Kim S, Chung J |title=An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat |journal=Pain |volume=50 |issue=3 |pages=355–63 |year=1992 |pmid=1333581 |doi=10.1016/0304-3959(92)90041-9|s2cid=216059787 }}{{cite journal |author=Malmberg A, Basbaum A |title=Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates |journal=Pain |volume=76 |issue=1–2 |pages=215–22 |year=1998 |pmid=9696476 | doi = 10.1016/S0304-3959(98)00045-1 |s2cid=23878913 }}{{cite journal |author=Sung B, Na H, Kim Y, Yoon Y, Han H, Nahm S, Hong S |title=Supraspinal involvement in the production of mechanical allodynia by spinal nerve injury in rats |journal=Neurosci. Lett. |volume=246 |issue=2 |pages=117–9 |year=1998 |pmid=9627194 | doi = 10.1016/S0304-3940(98)00235-3 |s2cid=36857086 }}{{cite journal |author=Lee B, Won R, Baik E, Lee S, Moon C |title=An animal model of neuropathic pain employing injury to the sciatic nerve branches |journal=NeuroReport |volume=11 |issue=4 |pages=657–61 |year=2000 |pmid=10757496 | doi = 10.1097/00001756-200003200-00002 |s2cid=40457392 }}{{cite journal |author=Decosterd I, Woolf C |title=Spared nerve injury: an animal model of persistent peripheral neuropathic pain |journal=Pain |volume=87 |issue=2 |pages=149–58 |year=2000 |pmid=10924808 | doi = 10.1016/S0304-3959(00)00276-1 |s2cid=24918287 }}{{cite journal |author=Vadakkan K, Jia Y, Zhuo M |title=A behavioral model of neuropathic pain induced by ligation of the common peroneal nerve in mice |journal=The Journal of Pain: Official Journal of the American Pain Society |volume=6 |issue=11 |pages=747–56 |year=2005 |doi=10.1016/j.jpain.2005.07.005 |pmid=16275599}}

Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Compounds such as duloxetine, venlafaxine, and milnacipran that block both serotonin reuptake and norepinephrine reuptake do improve neuropathic pain.

Tricyclic antidepressants may also work on sodium channels in peripheral nerves.

{{main|Anticonvulsants}}

Pregabalin (Lyrica) and gabapentin (Neurontin) work by blocking specific calcium channels on neurons. The actions of the anticonvulsants carbamazepine (Tegretol) and oxcarbazepine (Trileptal), especially effective on trigeminal neuralgia, are principally on sodium channels.

Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy

in that subgroup on antiretroviral therapy.Wiffen PJ, Rees J. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev. 2007;(2):CD006044.

{{main|Opioids}}

Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.

Several opioids, particularly methadone have NMDA antagonist activity in addition to their µ-opioid agonist properties.

Methadone and ketobemidone possess NMDA antagonsism. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist.{{cite journal |author=Davis AM, Inturrisi CE |title=d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia |journal=J. Pharmacol. Exp. Ther. |volume=289 |issue=2 |pages=1048–53 |year=1999 |pmid=10215686 |doi= |url=http://jpet.aspetjournals.org/cgi/content/full/289/2/1048}}

There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of NMDA antagonism. It is reasonable to base the choice of opioid on other factors.{{cite journal |author=Bruera E, Palmer JL, Bosnjak S, et al. |title=Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study |journal=J. Clin. Oncol. |volume=22 |issue=1 |pages=185–92 |year=2004 |pmid=14701781 |doi=10.1200/JCO.2004.03.172}}

In some forms of neuropathy, especially post-herpes neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.

Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers.{{cite journal |author=Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR |title=Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation |journal=Pain |volume=81 |issue=1–2 |pages=135–45 |year=1999 |pmid=10353501| doi = 10.1016/S0304-3959(99)00007-X |s2cid=8952555 }} Nevertheless, benefits appear to be modest.{{cite journal |author=Finnerup NB, Otto M, Jensen TS, Sindrup SH |title=An evidence-based algorithm for the treatment of neuropathic pain |journal=MedGenMed |volume=9 |issue=2 |pages=36 |year=2007 |pmid=17955091 |doi=|pmc=1994866 }}

Marijuana and its active ingredients are called cannabinoids. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult.{{cite journal |author=Ponto LL |title=Challenges of marijuana research |journal=Brain |volume=129 |issue=Pt 5 |pages=1081–3 |year=2006 |date=May 2006 |pmid=16627464 |doi=10.1093/brain/awl092}} Similar considerations apply to opioids.

A recent study showed smoked marijuana is beneficial in treating symptoms of HIV-associated peripheral neuropathy.{{cite journal |author=Abrams D, Jay C, Shade S, Vizoso H, Reda H, Press S, Kelly M, Rowbotham M, Petersen K |title=Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial |journal=Neurology |volume=68 |issue=7 |pages=515–21 |year=2007 |pmid=17296917 | doi = 10.1212/01.wnl.0000253187.66183.9c |s2cid=4845241 }}

Nabilone is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine.{{cite journal |author=Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D |title=Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study |journal=BMJ |volume=336 |issue=7637 |pages=199–201 |year=2008 |pmid=18182416 |doi=10.1136/bmj.39429.619653.80|pmc=2213874 }}

The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use.{{cite journal |author=Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ |title=Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review |journal=BMJ |volume=323 |issue=7303 |pages=13–6 |year=2001 |pmid=11440935| doi = 10.1136/bmj.323.7303.13 |pmc=34324 }} A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.{{cite journal |author=Wallace M, Schulteis G, Atkinson JH, et al. |title=Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers |journal=Anesthesiology |volume=107 |issue=5 |pages=785–96 |year=2007 |pmid=18073554 |doi=10.1097/01.anes.0000286986.92475.b7 |s2cid=15517673 }}

Sativex, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain.

{{cite web

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|title=Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis Drug Development Technology

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Long-term studies are needed to assess the probability of weight gain,{{cite journal |author=Vickers SP, Kennett GA |title=Cannabinoids and the regulation of ingestive behaviour |journal=Curr Drug Targets |volume=6 |issue=2 |pages=215–23 |year=2005 |date=March 2005 |pmid=15777191 |doi= 10.2174/1389450053174514|url=http://www.bentham-direct.org/pages/content.php?CDT/2005/}} unwanted psychological influences and other adverse effects.

{{Main|Botulinum toxin}}

Botulinum Toxin Type A (BTX-A) is best know by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.{{cite journal |author=Ranoux D, Attal N, Morain F, Bouhassira D |title=Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain |journal=Annals of Neurology |volume=64 |issue=3 |pages=274–83 |year=2008 |date=September 2008 |pmid=18546285 |doi=10.1002/ana.21427 |s2cid=205341110 |url=https://www.hal.inserm.fr/inserm-00292356/file/Ranouxetalrevised.pdf}}

The utility of BTX-A in other painful conditions remains to be established.{{cite journal |author=Naumann M, So Y, Argoff CE, et al. |title=Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology |journal=Neurology |volume=70 |issue=19 |pages=1707–14 |year=2008 |date=May 2008 |pmid=18458231 |doi=10.1212/01.wnl.0000311390.87642.d8 |url=}}

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.{{cite journal |author=Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB |title=High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia |journal=Neurology |volume=48 |issue=5 |pages=1212–8 |year=1997 |pmid=9153445 |doi=10.1212/wnl.48.5.1212|s2cid=25663595 }} Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by unacceptable side effects.

In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.

Lesioning operations on the sympathetic branch of the autonomic nervous system are sometimes carried out.

There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.{{cite journal |author=Head KA |title=Peripheral neuropathy: pathogenic mechanisms and alternative therapies |journal=Altern Med Rev |volume=11 |issue=4 |pages=294–329 |year=2006 |pmid=17176168 |doi= |url=http://www.thorne.com/altmedrev/.fulltext/11/4/294.pdf }}

A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.{{cite journal |author=Foster TS |title=Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy |journal=Diabetes Educ |volume=33 |issue=1 |pages=111–7 |year=2007 |pmid=17272797 |doi=10.1177/0145721706297450 |s2cid=22801230 |quote=ALA appears to improve neuropathic symptoms and deficits when administered via parenteral supplementation over a 3-week period. Oral treatment with ALA appears to have more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone.}} While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia),{{cite journal |author=Ziegler D, Ametov A, Barinov A, et al. |title=Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial |journal=Diabetes Care |volume=29 |issue=11 |pages=2365–70 |year=2006 |pmid=17065669 |doi=10.2337/dc06-1216|s2cid=16659120 }} the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone". There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.{{cite journal |author=Patton LL, Siegel MA, Benoliel R, De Laat A |title=Management of burning mouth syndrome: systematic review and management recommendations |journal=Oral Surg Oral Med Oral Pathol Oral Radiol Endod |volume=103 Suppl |issue= |pages=S39.e1–13 |year=2007 |pmid=17379153 |doi=10.1016/j.tripleo.2006.11.009}}

Benfotiamine is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.{{cite journal |author=Stracke H, Lindemann A, Federlin K |title=A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy |journal=Exp. Clin. Endocrinol. Diabetes |volume=104 |issue=4 |pages=311–6 |year=1996 |pmid=8886748 |doi=10.1055/s-0029-1211460}}{{cite journal |author=Thornalley PJ |title=The potential role of thiamine (vitamin B(1)) in diabetic complications |journal=Curr Diabetes Rev |volume=1 |issue=3 |pages=287–98 |year=2005 |pmid=18220605| doi = 10.2174/157339905774574383 }}

In addition to pharmacological treatment several other modalities are commonly recommended.{{cite journal |author=Chen H, Lamer TJ, Rho RH, et al. |title=Contemporary management of neuropathic pain for the primary care physician |journal=Mayo Clin. Proc. |volume=79 |issue=12 |pages=1533–45 |year=2004 |pmid=15595338 |doi=10.4065/79.12.1533}} While lacking adequate double blind trials, these have shown to reduce pain and improve patient quality of life for chronic neuropathic pain: chiropractic, yoga, massage, meditation, cognitive therapy,{{cite journal |author=Kerns JW, White A, Nashelsky J, Sherman S |title=Does psychiatric treatment help patients with intractable chronic pain? |journal=J Fam Pract |volume=55 |issue=3 |pages=235–6 |year=2006 |pmid=16510058 |doi= |url=http://www.jfponline.com/Pages.asp?AID=3897}} and prescribed exercise. Some pain management specialists will try acupuncture, with variable results.

Transcutaneous electrical nerve stimulation (TENS) may be worth considering in chronic neurogenic pain. TENS, with certain electrical waveforms, appears to have an acupuncture-like function.

Infrared photo therapy has been used to treat neuropathic symptoms.{{cite web |author=Burke T |title=Part 9. How Light (Photo Energy) May Increase Local NO and Vasodilation |work=Nitric Oxide and Its Role in Health and Diabetes |url=http://www.diabetesincontrol.com/burkearchive/nitricoxide9.shtml |publisher=Diabetes In Control |accessdate=2008-03-28}} However, recent work has cast doubt on the value of this approach.{{cite journal |author=Lavery LA, Murdoch DP, Williams J, Lavery DC |title=Does anodyne light therapy improve peripheral neuropathy in diabetes? A double-blind, sham-controlled, randomized trial to evaluate monochromatic infrared photoenergy |journal=Diabetes Care |volume=31 |issue=2 |pages=316–21 |year=2008 |pmid=17977931 |doi=10.2337/dc07-1794|s2cid=15382069 }}

Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.Krames ES. Neuromodulatory devices are part of our "Tools of the Trade". Pain Med 2006;7:S3-5.

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 for which they might be beneficial.

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. Lack of pain relief sometimes prompts device removal.{{cite journal |author=Turner JA, Loeser JD, Deyo RA, Sanders SB |title=Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications |journal=Pain |volume=108 |issue=1–2 |pages=137–47 |year=2004 |pmid=15109517 |doi=10.1016/j.pain.2003.12.016|s2cid=16722691 }}

Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide{{cite journal |author=Lynch SS, Cheng CM, Yee JL |title=Intrathecal ziconotide for refractory chronic pain |journal=Ann Pharmacother |volume=40 |issue=7–8 |pages=1293–300 |year=2006 |pmid=16849624 |doi=10.1345/aph.1G584|s2cid=1159955 }} are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted.

There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time.{{cite journal |author=Turner JA, Sears JM, Loeser JD |title=Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications |journal=Clin J Pain |volume=23 |issue=2 |pages=180–95 |year=2007 |pmid=17237668 |doi=10.1097/01.ajp.0000210955.93878.44|s2cid=22913374 }} These results must be viewed skeptically since placebo effects cannot be evaluated.

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 requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.Brown JA, Pilitsis JG. Motor Cortex Stimulation

Pain Medicine 2006; 7:S140.

Osenbach, R. Neurostimulation for the Treatment of Intractable Facial Pain

Pain Medicine 2006; 7:S126

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%).{{cite journal |author=Bittar RG, Kar-Purkayastha I, Owen SL, et al. |title=Deep brain stimulation for pain relief: a meta-analysis |journal=J Clin Neurosci |volume=12 |issue=5 |pages=515–9 |year=2005 |pmid=15993077 |doi=10.1016/j.jocn.2004.10.005|s2cid=24246117 }} There is a significant complication rate which increase over time.{{cite journal |author=Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM |title=Long-term hardware-related complications of deep brain stimulation |journal=Neurosurgery |volume=50 |issue=6 |pages=1268–74; discussion 1274–6 |year=2002 |pmid=12015845| doi = 10.1097/00006123-200206000-00017 |s2cid=36904630 }}

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