AdvancesinNeuropathicPain
SECTION EDITOR:DAVID E.PLEASURE,MD
Advances in Neuropathic Pain
Diagnosis,Mechanisms,and Treatment Recommendations
Robert H.Dworkin,PhD;Miroslav Backonja,MD;Michael C.Rowbotham,MD;Robert R.Allen,MD;
Charles R.Argoff,MD;Gary J.Bennett,PhD;M.Catherine Bushnell,PhD;John T.Farrar,MD;Bradley S.Galer,MD; Jennifer A.Haythornthwaite,PhD;David J.Hewitt,MD;John D.Loeser,MD;Mitchell B.Max,MD;
Mario Saltarelli,MD,PhD;Kenneth E.Schmader,MD;Christoph Stein,MD;David Thompson,PhD;
Dennis C.Turk,PhD;Mark S.Wallace,MD;Linda R.Watkins,PhD;Sharon M.Weinstein,MD
C hronic neuropathic pain,caused by lesions in the peripheral or central nervous sys-
tem,comes in many forms.We describe current approaches to the diagnosis and as-
sessment of neuropathic pain and discuss the results of recent research on its patho-
physiologic mechanisms.Randomized controlled clinical trials of gabapentin,the5% lidocaine patch,opioid analgesics,tramadol hydrochloride,and tricyclic antidepressants provide an evidence-based approach to the treatment of neuropathic pain,and specific recommendations are presented for use of these medications.Continued progress in basic and clinical research on the pathophysiologic mechanisms of neuropathic pain may make it possible to predict effective treatments for individual patients by application of a pain mechanism–based approach.
Arch Neurol.2003;60:1524-1534
Chronic neuropathic pain is common in clinical practice.Patients with conditions as diverse as diabetic polyneuropathy,hu-man immunodeficiency virus(HIV)sen-sory neuropathy,poststroke syndromes, and multiple sclerosis frequently experi-ence daily pain that greatly impairs their quality of life.Table1divides common chronic neuropathic pain syndromes into 2groups based on a central or peripheral location of the nervous system lesion.It is probable,however,that both peripheral and central nervous system mechanisms con-tribute to the persistence of most types of neuropathic pain.Although precise esti-mates of the prevalence of neuropathic pain are not available,it is more common than
has generally been appreciated.In the United States,there may be more than3 million people with painful diabetic neu-ropathy(PDN)1and as many as1million with postherpetic neuralgia(PHN).2 An evidence-based treatment ap-proach is becoming feasible as the num-ber of published randomized controlled trials continues to grow steadily.In this article,we discuss the diagnosis and as-sessment of neuropathic pain and survey recent research on pathophysiologic mechanisms.Evidence-based treatment recommendations for the pharmacologic management of chronic neuropathic pain are presented that take into account clini-cal effectiveness,adverse effects,influ-ence on quality of life,and cost.
DIAGNOSIS AND ASSESSMENT Neuropathic pain syndromes typically have both negative and positive sensory symp-toms and signs.3Nonsensory neurologi-cal symptoms and signs depend on the un-derlying cause and may independently contribute to pain and disability.Al-though neuropathic pain has been de-fined by the International Association for the Study of Pain as pain“initiated or caused by a primary lesion or dysfunc-tion in the nervous system,”4(p212)several investigators have recently argued that the inclusion of the term dysfunction makes this definition vague and unacceptably broad.5,6A proposed solution is to define neuropathic pain as pain caused by a le-sion of the peripheral or central nervous
For editorial comment
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NEUROLOGICAL REVIEW
system(or both)manifesting with sensory symptoms and signs.6Underlying causes include infections,trauma, metabolic abnormalities,chemotherapy,surgery,irra-diation,neurotoxins,inherited neurodegeneration,nerve compression,inflammation,and tumor infiltration.Dem-onstrating a lesion of the nervous system compatible with particular symptoms and signs provides strong support for considering the pain to be neuropathic.However,when no lesion can be demonstrated,the limits of current di-agnostic technology do not always allow the possibility of neuropathic pain to be excluded.The diagnosis of neu-ropathic pain is based on a medical history,review of sys-tems,physical and neurological examination,and ap-propriate laboratory studies including blood and serologic tests,magnetic resonance imaging,and electrophysi-ologic studies.3In some instances,nerve or skin biopsy is necessary to directly visualize nerve fibers.
Evaluation of Pain and Other Symptoms
The assessment of pain and other symptoms is needed for diagnosis and to guide therapy.No single symptom or sign is pathognomonic.Because neuropathic pain is the result of disease or injury to the nervous system,clini-cal manifestations typically include both negative and posi-tive sensory symptoms and signs.Motor symptoms and signs are often present,but these deficits can be very subtle.
A distinction should be made between stimulus-evoked pain and spontaneous(stimulus-independent)pain, which may have different underlying mechanisms.7Spon-
taneous pain can be either constant or intermittent(even paroxysmal),and most patients describe having both(eg, constant“burning”pain plus intermittent pain that is “shooting”or“electric shock–like”).In addition,sponta-neous paresthesias and dysesthesias manifest as abnor-mal sensations,including crawling,numbness,itching,and tingling.When obtaining the patient’s history,it is im-portant to assess the intensity,quality,and duration of spon-taneous pain and abnormal sensations.The topographi-cal distribution is especially helpful in guiding the neurological examination.
Pain may be evoked by everyday environmental stimuli such as the gentle touch and pressure of cloth-ing,wind,riding in a car,and hot and cold https://www.wendangku.net/doc/ac2409650.html,mon neurological examination tools,includ-ing a cotton wisp,a foam brush,a tuning fork,and cold and warm water–filled tubes,can be used to mimic these stimuli.
Pain intensity can be rated with any of several reli-able and validated verbal,numerical,or visual analog scales.Patients rate their pain using some type of con-tinuum(eg,“no pain”to“worst possible pain”).8The of-ten unusual abnormal sensations in patients with neu-ropathic pain can be assessed with measures of pain quality such as the Neuropathic Pain Scale9and Neuropathic Pain Questionnaire.10Chronic pain has a significant negative effect on quality of life,and various measures of physi-cal and emotional function can also be used to evaluate a patient’s response to treatment.11Assessment of psy-chological comorbidity(eg,depression or anxiety),sleep disturbance,work-related issues,treatment expecta-tions,rehabilitative needs,and the availability of social support from family and friends should not be over-looked.12
Physical Examination
A thorough physical and neurological examination can help determine where the lesion is and assess nonneu-ropathic contributions to the patient’s pain,most com-monly musculoskeletal,inflammatory,myofascial,and psychological processes.3When combined with a his-tory and laboratory tests suggesting a specific cause,the finding of negative and positive sensory phenomena in the same area innervated by damaged nervous system pathways usually confirms the diagnosis.
Patients may have sensory deficits with one modal-ity,such as pinprick sensitivity,and hyperalgesia to an-other,such as light touch,in the same nerve distribu-tion.Whereas the physician may have difficulty recognizing this paradoxical finding,patients are even more confused by the complexity of their sensory expe-riences;they often have trouble describing the unusual nature of their symptoms and fear that they will not be believed.For patients to be good sensory witnesses and provide all of the necessary information,they need to be reassured as well as instructed to carefully describe their symptoms and rate the severity of their abnormal sen-sations.When specific stimuli in the standard neuro-logical sensory examination are applied first to the un-affected area and then to the area affected by pain,patients
Abbreviation:HIV,human immunodeficiency virus.
should be instructed to first respond in simple terms—that is,whether the stimulus applied to the painful area causes the same sensation as in the unaffected area or whether it is less or more intense—before describing their perception of the quality of the stimulus.For example, pinprick may be more painful(hyperalgesia)but less sharp because of the underlying sensory deficit.
Pain in response to a normally nonnoxious stimu-lus is termed allodynia.Dynamic mechanical allodynia can be elicited by lightly rubbing or brushing the skin with a cotton swab or brush,static mechanical allo-dynia can be provoked by blunt pressure with a finger, and thermal allodynia can be assessed with a warm or cool tuning fork.An increased sensation of pain in re-sponse to a normally painful stimulus is termed hyper-algesia,which can be assessed using painful thermal(cold or heat)or punctate(eg,pinprick)stimuli.Painful sum-mation and hyperpathia to repeated stimuli,especially when the initial sensation is reduced,is important evi-dence of abnormal sensory processing.
Nonsensory neurological and musculoskeletal symp-toms may contribute strongly to overall disability.Mo-tor system symptoms and signs include weakness,fati-gability,hypotonia,tremor,dystonia,spasticity,ataxia, apraxia,and motor neglect.Other musculoskeletal symp-toms and signs include decreased range of motion,stiff-ness of joints,spontaneous muscle spasms,localized muscle tenderness,and myofascial trigger points.
Ancillary Studies
There is no single diagnostic test for neuropathic pain or pain in general.Ancillary studies can confirm or ex-clude underlying causes and suggest disease-specific treat-ments,such as for diabetes mellitus in patients with pain-ful neuropathy or spinal disorders in patients with radiculopathy.To assess peripheral nerve function,nerve conduction velocity tests and electromyography pro-vide information about large myelinated peripheral nerve function but do not test smaller myelinated or unmy-elinated nerve fibers carrying pain and temperature in-formation.Quantitative thermal sensory testing relies on the patient’s psychophysical ability to discriminate be-tween fine changes in thermal stimuli;it is not widely used because it requires specialized equipment and train-ing.Magnetic resonance imaging assesses anatomical in-tegrity of thermonociceptive sensory-processing re-gions such as the brainstem,thalamus,sensory cortex, anterior cingulate,and insular cortex,which can con-tribute to central neuropathic pain when injured.Func-tional magnetic resonance imaging can further assess these and other pain-related structures,but its role in clinical practice will remain limited in the near future.
Diagnosing neuropathic pain can be difficult.For example,in radicular neck and low back pain,there is a significant neuropathic component from the nerve root injury,but mechanical instability or secondary myofas-cial pain may mask this component.Physicians should also keep in mind that psychosocial factors are a major component of the experience of chronic pain and should be routinely addressed when patients are evaluated.Psy-chological processes such as anxiety can influence the report of pain and in rare instances produce exagger-ated responses.However,sincerely communicating that the patient’s pain is taken seriously and providing clear instructions will minimize the possibility that the neu-rological examination is unreliable or uninterpretable be-cause of psychological processes.When combined with a long history of multiple unexplained pain problems, somatization disorder or another psychiatric diagnosis is possible.Proper diagnosis is the cornerstone of effec-tive treatment,and complex patterns of signs and symp-toms may necessitate the involvement of multiple medi-cal specialties.
PATHOPHYSIOLOGIC MECHANISMS
Our ability to translate pain complaints and sensory find-ings into specific pathophysiologic mechanisms that have treatment implications is in its infancy.13-16Clinical inves-tigations of pain mechanisms are labor intensive and re-quire specialized equipment;thus,they are not yet prac-tical for routine clinical use.Even in specialized pain research settings,it is difficult to identify specific neuro-pathic pain mechanisms.A simple focal peripheral nerve injury unleashes a range of peripheral and central ner-vous system processes that can all contribute to persis-tent pain and abnormal sensation.Inflammation,repara-tory mechanisms of neural tissues in response to injury, and the reaction of adjacent tissues to injury lead to a state of hyperexcitability in primary afferent nociceptors,a phe-nomenon termed peripheral sensitization.In turn,central neurons innervated by such nociceptors undergo dra-matic functional changes including a state of hyperexcit-ability termed central sensitization.Normally these sensi-tization phenomena extinguish themselves as the tissue heals and inflammation subsides.However,when pri-mary afferent function is altered in an enduring way by injury or disease of the nervous system,these processes persist and may be highly resistant to treatment.
Injury or permanent loss of primary afferent fibers (deafferentation)differentiates peripheral neuropathic pain from other types of pain.Positive sensory phenom-ena(spontaneous pain,allodynia,and hyperalgesia)that are characteristic of patients with neuropathic pain are likely to have many underlying mechanisms,including ectopic generation of impulses as well as the de novo ex-pression of neurotransmitters and their receptors and ion channels.Direct injury to central structures may perma-nently alter sensory processing,and in some patients it causes central neuropathic pain and dysesthesias.The mechanisms underlying central neuropathic pain,how-ever,are still unclear.
An oversimplified but useful approach is to distin-guish processes that involve the following:(1)in-creased primary afferent nociceptor firing(eg,as a re-sult of abnormal collections of sodium channels in damaged peripheral nerve fibers,causing ectopic dis-charge);(2)decreased inhibition of neuronal activity in central structures(eg,due to loss of inhibitory neu-rons);and(3)altered central processing(central sensi-tization)so that normal sensory input is amplified and sustained.A continuum that has been explored in PHN has“irritability”of the nociceptive system at one end and
deafferentation at the other.15,16Although the ends of the continuum can be differentiated by clinical examina-tion and response to a brief focal application of topical capsaicin(capsaicin response test),the treatment impli-cations of this differentiation remain to be explored.17The contributions of other peripheral processes remain poorly understood.For example,the sympathetic nervous sys-tem may facilitate persistent abnormal primary afferent nociceptor activity following nerve injury,18and nerve injury and inflammation during the acute phase of her-pes zoster may be followed by a mixture of abnormal re-generation and receptor expression and permanent cu-taneous afferent loss in patients with PHN.19
Although the many mechanisms identified in ani-mal models of neuropathic pain still require translation and confirmation in human neuropathic pain syn-dromes,the results from these models provide valuable insights into diverse manifestations of neuropathic pain. Human laboratory studies,20-22although limited in num-ber,support the idea that the pathophysiologic mecha-nisms discovered in animal models are relevant to our understanding of human neuropathic pain.
TREATMENT RECOMMENDATIONS Members of the faculty of the Fourth International Con-ference on the Mechanisms and Treatment of Neuro-pathic Pain participated in a meeting supported by an un-restricted educational grant to the University of Rochester Office of Professional Education(Rochester,NY)from Endo Pharmaceuticals(Chadds Ford,Pa)and contrib-uted as authors to the preparation of this article.Spe-cialties represented include anesthesiology,basic neu-roscience,epidemiology,geriatrics,internal medicine, neurology,neurosurgery,outcomes research,pharma-coeconomics,and psychology.MEDLINE searches,ex-amination of reference lists of published articles and book chapters,and personal knowledge of the literature were used to identify material relevant to developing treat-ment recommendations for patients with neuropathic pain.This material included systematic literature re-views,reports of randomized clinical trials,and publi-cations discussing the development and evaluation of clini-cal guidelines.
General Considerations
To evaluate changes in pain intensity during treatment, an11-point numerical rating scale in which0equals“no pain”and10equals“worst possible pain”is widely used to assess the patient’s level of pain currently,during the past day,or during the past week.Recent data suggest that a reduction of30%on such a scale is clinically im-portant and equivalent to categorical ratings of“moder-ate relief”or“much improved.”23The first-line treat-ments discussed as follows have all been demonstrated to provide statistically significant and clinically mean-ingful treatment benefits compared with placebo in mul-tiple randomized controlled trials.Benefits of pharma-cotherapy for improving quality of life,including physical and emotional function,have been found less consis-tently than for reducing pain intensity.Although the ef-ficacy of treatments have been compared by evaluating the number needed to treat,24-28the small sample sizes and methodological shortcomings of some trials limit con-fidence in such comparisons.
Drug-related adverse effects are common in the treat-ment of neuropathic pain,not only because of the specific medications used but also because many patients with this condition are older,take other medications,and have co-morbid illnesses.On the basis of our clinical experience and analyses of the number needed to harm,24,25,27we con-sidered safety,adverse effects,and drug interactions in the development of our recommendations.
Most randomized controlled trials of chronic neuro-pathic pain have examined only2pain syndromes,PDN and PHN.Moreover,the US Food and Drug Administra-tion(FDA)has approved medications for the treatment of only2specific neuropathic pain syndromes:trigemi-nal neuralgia(carbamazepine)and PHN(gabapentin and the5%lidocaine patch).The applicability of the results of clinical trials for one chronic neuropathic pain syn-drome to others cannot be determined,but most of the first-line therapies discussed as follows have been tested with multiple types of neuropathic pain and have shown similar results.26Medications with minimal risk that have demonstrated efficacy for1or more(ideally related)neu-ropathic pain syndromes are preferred.When efficacy has not been established,acceptable safety and tolerability in light of the patient’s medical condition,age,pain sever-ity,and previous treatment history are paramount.
Five caveats are required before presenting our treat-ment recommendations.First,these recommendations may apply to complex regional pain syndrome type I,al-though controlled trials of first-line medications are lack-ing;this pain syndrome is believed to be due to nervous system dysfunction without permanent injury to a nerve trunk.Second,although chronic neuropathic back pain (ie,cervical and lumbar radiculopathic pain)is prob-ably the most prevalent pain syndrome to which neuro-pathic mechanisms contribute,there are no accepted di-agnostic criteria for identifying this neuropathic component.It is likely that a combination of neuro-pathic,skeletal,and myofascial mechanisms account for this type of pain in many patients.Subgroup analyses of a randomized placebo-controlled trial suggested that pa-tients who had chronic radicular low back pain re-sponded best to treatment with nortriptyline hydrochlo-ride,29one of the first-line medications discussed as follows.Third,distinct treatment guidelines for tic dou-loureux(trigeminal neuralgia)emphasize carbamaze-pine,phenytoin,and baclofen.30Fourth,we acknowl-edge that pharmacologic management is not a cure and should be considered an integral component of a more comprehensive approach to treatment.A discussion of the many widely used nonpharmacologic approaches in-cluding physical therapy,psychological treatments,in-vasive procedures(eg,neural blockade or dorsal col-umn stimulation),and various complementary and alternative medicine interventions is beyond the scope of this review.Fifth,we assume that pharmacotherapy will be used within a treatment context in which educa-tion,support,and reassurance characterize the relation-ship between the patient and physician.We strongly rec-
ommend that the dosage be adjusted as necessary based on frequent and careful evaluation of adverse effects,treat-ment adherence,and pain relief.
Review and Specific Recommendations
Recommendations for first-line pharmacologic treat-ments are based on positive results from multiple ran-domized controlled trials,and recommendations for second-line pharmacologic treatments are based on the positive result of a single randomized controlled trial or inconsistent results of multiple randomized controlled trials(with1exception,discussed as follows).The re-sults of published trials and our clinical experience pro-vide the foundation for our specific recommendations for first-line treatments.
First-line Medications.The efficacy of gabapentin,the 5%lidocaine patch,opioid analgesics,tramadol hydro-chloride,and tricyclic antidepressants(TCAs)has been consistently demonstrated in multiple randomized con-trolled trials.Each one can be used as an initial treat-ment for neuropathic pain in certain clinical circum-stances.Opioid analgesics and TCAs generally require greater caution than the other options.For each of these 5medications,brief reviews of the relevant randomized clinical trials and specific treatment recommendations fol-low.Treatment recommendations are summarized in Table2.
Gabapentin.There are8published double-blind, placebo-controlled randomized clinical trials of gabap-entin for chronic neuropathic pain.These studies exam-ined patients with PHN,PDN,mixed neuropathic pain syndromes,phantom limb pain,Guillain-Barre′syn-drome,and acute and chronic pain from spinal cord in-jury.31-38Gabapentin at dosages up to3600mg/d signifi-cantly reduced pain compared with placebo; improvements in sleep,mood,and quality of life were also demonstrated in some trials.In2trials of PDN and spinal cord injury pain with small sample sizes or rela-tively lower dosages,evidence of efficacy was more lim-ited.33,38On the basis of the results of2large random-ized trials,32,34the FDA approved gabapentin for the treatment of PHN.
The adverse effects of gabapentin include somno-lence and dizziness and,less commonly,gastrointesti-nal symptoms and mild peripheral edema.All of these effects require monitoring and dosage adjustment but usu-ally not discontinuation of the drug.Gabapentin may cause or exacerbate gait and balance problems as well as cognitive impairment in elderly patients,and dosage ad-justment is necessary in patients with renal insuffi-ciency.However,its generally excellent tolerability,safety, and lack of drug interactions distinguish gabapentin from most other oral medications used for the treatment of chronic neuropathic pain.
To decrease adverse effects and increase patient ad-herence to treatment,gabapentin should be initiated at low dosages—100to300mg in a single dose at bedtime or100to300mg3times daily—and then titrated every 1to7days by100to300mg as tolerated.Although3 times daily is the target dosage,more rapid titration may be accomplished if most of the daily dose is initially given at bedtime to limit daytime sedation.Target dosages that demonstrated benefits of gabapentin treatment for neu-ropathic pain ranged from1800mg/d(the FDA-approved dosage for PHN)to3600mg/d.If only partial relief of pain occurs at1800mg/d,titration can be con-tinued up to3600mg/d(1200mg3times daily)as tol-erated.The final dosage should be determined either by achieving complete pain relief or by the development of unacceptable adverse effects that do not resolve promptly. An adequate trial of gabapentin would include3to8weeks for titration to allow the development of tolerance to ad-verse effects,plus1to2weeks at the maximum toler-ated dosage.
*Dosages given are for morphine sulfate.
5%Lidocaine Patch.There are2published double-blind,randomized,vehicle-controlled clinical trials of the 5%lidocaine patch in patients with PHN.39,40In these stud-ies,patients obtained statistically significantly greater pain relief with the5%lidocaine patch compared with vehicle-controlled patches containing no lidocaine.On the ba-sis of these results,the FDA approved the5%lidocaine patch for the treatment of PHN.Notably,the efficacy of this treatment has been demonstrated only in patients with PHN and allodynia,and no controlled studies have been conducted for other pain conditions.Anecdotal evi-dence of a beneficial effect in patients who have other types of neuropathic pain with allodynia has been pub-lished.41
The5%lidocaine patch is a topical preparation.In patients with normal hepatic function,blood levels of the drug are minimal,and accumulation does not occur with a dosage schedule of12hours on,12hours off.Because of this,the5%lidocaine patch has excellent safety and tol-erability,and the only adverse effects involve mild skin reactions(eg,erythema or rash).Systemic absorption from the patch must be considered in patients receiving oral class 1antiarrhythmic drugs(eg,mexiletine hydrochloride).
Treatment with the5%lidocaine patch consists of the application of no more than3patches daily for a maxi-mum of12hours,with the patch applied directly to the area of maximal pain(the FDA-approved dosage for PHN). Titration of the5%lidocaine patch is not necessary,and an adequate trial would last2weeks.
Opioid Analgesics.Five double-blind randomized trials of oral opioid analgesics have been published since 1998.In patients with PHN,controlled-release oxy-codone hydrochloride titrated to a maximum dosage of 60mg/d significantly relieved pain,disability,and allo-dynia compared with placebo.42In patients with PDN, controlled-release oxycodone titrated to a maximum dosage of120mg/d significantly improved pain,the per-formance of daily activities,and sleep compared with pla-cebo;the average dosage of oxycodone in that trial was 37mg/d(range,10-99mg/d).43Controlled-release mor-phine sulfate titrated to a maximum dosage of300mg/d was superior to placebo in patients with phantom limb pain.44
In a unique3-period crossover study comparing treat-ment with opioid analgesics,TCAs,and placebo in pa-tients with PHN,controlled-release morphine sulfate ti-trated to a maximum dosage of240mg/d provided statistically significant benefits for pain and sleep but not for physical function and mood.45In that trial,patients pre-ferred treatment with opioid analgesics compared with TCAs and placebo despite a greater incidence of adverse effects and more dropouts during opioid treatment.In a double-blind randomized study that compared2differ-ent dosages of levorphanol tartrate in patients with a va-riety of peripheral and central neuropathic pain syn-dromes,patients receiving the higher dosage reported significantly greater pain reduction,but there were no dif-ferences between groups in mood,sleep,or interference with daily activities.46In that study,patients with central poststroke pain were the least likely to report improve-ment;only30%with this disorder completed the trial.No-tably,measures of cognitive function were administered in2of these studies,and it was reported that treatment with opioid analgesics did not impair performance.45,46Con-sidered together,the results of these5studies provide a reliable base of evidence for considering opioid analge-sics to be a first-line treatment for neuropathic pain.
The most common adverse effects of opioid analge-sics are constipation,sedation,and nausea;these effects most likely contributed to the relatively high withdrawal rates found in the placebo-controlled trials.In elderly pa-tients treated with opioid analgesics,cognitive impair-ment and problems with mobility can occur,which may contribute to an increased risk of hip fracture.Most pa-tients become tolerant to these adverse effects,although constipation often persists.Regular laxative therapy or switching to transdermal fentanyl citrate may help re-duce constipation.Opioid analgesics must be used cau-tiously in patients with a history of substance abuse or at-tempted suicide,and accidental death or suicide can occur with overdose.Although patients treated with opioid an-algesics may develop analgesic tolerance(ie,a reduction in analgesic benefit with time),in responsive patients a stable dosage can usually be achieved.All patients taking opioid analgesics develop physical dependence(with-drawal symptoms with abrupt discontinuation of the drug or rapid dose reduction)and must be advised not to abruptly discontinue their medication.
The risk that substance abuse,a maladaptive pat-tern of substance use leading to clinically significant im-pairment or distress,will develop in patients with neu-ropathic pain who do not have a history of substance abuse is unknown but probably low.Opioid abuse must be dis-tinguished from the appropriate desire to continue tak-ing medication that effectively relieves pain and from ap-prehension about not having adequate access to medications that are often difficult to obtain.There is a substantial risk in prescribing opioids to patients with a history of substance abuse;doing so requires very close monitoring.Concerns about causing a substance abuse disorder when there is no history of one do not justify refraining from using opioid analgesics in patients with chronic neuropathic pain.
Numerous short-and long-acting opioid analge-sics are available.We hold diverse opinions regarding the algorithm for administering opioids for neuropathic pain. One approach recommended by many of us is to begin treatment with opioid analgesics using a short-acting medication at dosages equianalgesic to the oral admin-istration of morphine sulfate at5to15mg every4hours as https://www.wendangku.net/doc/ac2409650.html,monly used short-acting opioid analge-sics include oxycodone alone and hydrocodone bitar-trate and oxycodone in combination with acetamino-phen,aspirin,or ibuprofen(a morphine elixir can be used with patients who have difficulty swallowing).
After1to2weeks of treatment,the patient’s total daily dosage of a short-acting opioid analgesic can be con-verted to an equianalgesic daily dosage of one of the long-acting opioid analgesics such as controlled-release mor-phine,controlled-release oxycodone,transdermal fentanyl, levorphanol,or methadone hydrochloride.Limited ac-cess to short-acting medication for breakthrough pain may be appropriate.Conversion of the patient’s treatment regi-men from short-acting to long-acting medication may re-
quire considerable dosage adjustment for1to2weeks. Once the patient is receiving a stable dosage of a long-acting medication,an adequate trial of an opioid anal-gesic requires4to6weeks to assess both pain and func-tion.Pain reduction without improvement in function indicates a need to consider modifying treatment.With careful titration and monitoring,there is no clear maxi-mum dosage of opioid analgesics.However,evaluation by a pain specialist may be considered when morphine sulfate equianalgesic dosages exceeding120to180mg/d are contemplated.The benefits of levels higher than180 mg/d in patients with neuropathic pain have not been es-tablished in double-blind trials.
Careful documentation and appropriate monitor-ing of treatment are important for the safe and effective use of opioid analgesics.Model guidelines for the use of controlled substances for the treatment of pain have been adopted by the Federation of State Medical Boards of the United States,and the US Drug Enforcement Adminis-tration has recognized that the use of opioid analgesics is appropriate for treating chronic pain.
Tramadol.Tramadol is a norepinephrine and sero-tonin reuptake inhibitor with a major metabolite that is aμopioid agonist.There are2published double-blind, placebo-controlled randomized clinical trials of trama-dol for neuropathic pain,1in patients with PDN and1 in patients with painful polyneuropathy of various causes, including PDN.47,48In both trials,tramadol hydrochlo-ride titrated to a maximum dosage of400mg/d signifi-cantly relieved pain compared with placebo.Beneficial effects of tramadol treatment on allodynia48and quality of life47were also reported.
The adverse effects of tramadol include dizziness,nau-sea,constipation,somnolence,and orthostatic hypoten-sion.These occur more frequently when the dosage is es-calated rapidly and with concurrent administration of other drugs that have similar adverse-effect profiles.There is an increased risk of seizures in patients treated with trama-dol who have a history of seizures or who are also receiv-ing antidepressants,opioids,neuroleptics,or other drugs that can reduce the seizure threshold.Serotonin syn-drome may occur if tramadol is used concurrently with other serotonergic medications,especially selective serotonin re-uptake inhibitors(SSRIs)and monoamine oxidase inhibi-tors.Tramadol may cause or exacerbate cognitive impair-ment in elderly patients,and dosage adjustment is necessary in patients with renal or hepatic disease.Abuse of trama-dol is considered rare but has been observed.
To decrease the likelihood of adverse effects and in-crease patient adherence to treatment,tramadol should be initiated at low dosages—50mg once or twice daily—and then titrated every3to7days by50to100mg/d in divided doses as tolerated.The maximum dosage of tra-madol hydrochloride is100mg4times daily(in pa-tients older than75years,300mg/d in divided doses), and an adequate trial requires4weeks.
Tricyclic Antidepressants.The first medication cat-egory that proved effective for neuropathic pain in placebo-controlled trials was TCAs.25-28Although clini-cal trials of patients with HIV sensory neuropathy,49,50pain from spinal cord injury,51and cisplatin-induced neu-ropathy52found little benefit of treatment with amitrip-tyline hydrochloride when compared with placebo,an apt summary of the overall efficacy of TCAs in neuro-pathic pain is provided by the title of a review by Max.53 The primary problem with the use of TCAs is their adverse-effect profile;TCAs must be used cautiously in patients with a history of cardiovascular disease,glau-coma,urinary retention,or autonomic neuropathy.Al-most20%of patients treated with nortriptyline after a myocardial infarction developed adverse cardiac events in a recent study.54Consequently,a screening electro-cardiogram to check for cardiac conduction abnormali-ties is recommended before beginning treatment with TCAs,especially in patients older than40years.As with opioid analgesics,TCAs must be used cautiously when there is a risk of suicide or accidental death from over-dose.They may block the effects of certain antihyper-tensive drugs(eg,clonidine or guanethidine),and they interact with drugs metabolized by cytochrome P4502D6 (eg,cimetidine,phenothiazines,and class1C antiarrhythmics).All SSRIs inhibit cytochrome P4502D6, and to prevent toxic concentrations of TCAs in the plasma, caution must be exercised in the concomitant adminis-tration of TCAs and SSRIs and when switching from one drug class to the other.In elderly patients,TCAs may cause balance problems and cognitive https://www.wendangku.net/doc/ac2409650.html,der ad-verse effects of TCAs include sedation,anticholinergic effects(eg,dry mouth or constipation),postural hypo-tension,and weight gain.
Although most clinical trials of TCAs for neuro-pathic pain have examined amitriptyline,this drug is not recommended in elderly patients because of the risk of significant adverse events.Nortriptyline and desipra-mine hydrochloride have fewer adverse effects and are generally better tolerated than amitriptyline.In a recent randomized double-blind trial,nortriptyline was found to provide equivalent analgesic benefits in patients with PHN when directly compared with amitriptyline but was better tolerated.55
Patients must understand that TCAs have an anal-gesic effect that has been demonstrated to be indepen-dent of their antidepressant effect.To decrease adverse effects and increase patient adherence to treatment,TCAs should be initiated at low dosages—10to25mg in a single dose at bedtime—and then titrated every3to7days by 10to25mg/d as tolerated.Although the analgesic effect of TCAs has been thought to occur at lower dosages than the antidepressant effect,there is no systematic evi-dence of this.However,some data are consistent with a dose-response relationship;TCAs should be titrated to dosages of75to150mg/d as tolerated.If a blood level of approximately100ng/mL of the active drug and its metabolite is not found at dosages of100to150mg,ti-tration can be continued further with caution.Blood lev-els of500ng/mL or higher of the active drug and its me-tabolite are associated with toxicity,and for titration higher than100to150mg/d,blood levels should be monitored and an electrocardiogram performed.An adequate trial of a TCA would last6to8weeks with at least1to2weeks at the maximum tolerated dosage.
Selecting a First-line Medication.Medication acquisi-tion costs vary greatly by geographic region,insurance
plan,industry health plan contracts,and availability of pharmaceutical company programs for patients without drug benefit plans.Physicians should become as famil-iar as possible with the acquisition costs of the medica-tions they prescribe and with the reimbursements pro-vided by their patients’insurance plans.Doing so will not only benefit the finances of their patients but will also maximize adherence to treatment recommendations.Con-sideration should be given to the availability of generic versions of medications used in treating chronic neuro-pathic pain.Tramadol,TCAs,and some opioid analge-sics are available in generic forms with acquisition costs considerably lower than the2first-line medications that are still protected by patent:gabapentin and the5%li-docaine patch.
Tricyclic antidepressants must be used with ex-treme caution in elderly patients because of the risk of toxic adverse effects to the heart and anticholinergic ad-verse effects.In addition,gabapentin,opioid analgesics, tramadol,and TCAs must all be used with caution in older patients because of the risk of falls and cognitive impair-ment.
Tricyclic antidepressants have numerous contrain-dications,especially in patients with cardiovascular dis-ease,because of the risks of conduction defects,arrhyth-mias,tachycardia,stroke,and acute myocardial infarction. In patients with renal insufficiency,the dosage of gaba-pentin or tramadol must be adjusted;in patients with he-patic disease,dosage adjustment of tramadol is neces-sary.Opioid analgesics must be used with caution in patients with a history of substance abuse.
Tricyclic antidepressants may be especially useful for treating depression in patients with chronic pain,but the risk of intentional overdose must be kept in mind; there is a much higher risk of suicide with TCAs com-pared with other antidepressants.In addition,many pa-tients with chronic pain have disturbed sleep,and trials of gabapentin and TCAs have demonstrated improve-ments in this area.
Many patients with neuropathic pain also have non-neuropathic pain(eg,osteoarthritis),and opioid analge-sics and tramadol have demonstrated efficacy in the treat-ment of both types.It has been suggested that TCAs should be used in treating constant pain and that carbamazepine-like anticonvulsants should be used for lancinating pain. However,the results of the randomized controlled trials of TCAs and anticonvulsants that have systematically as-sessed pain quality show no evidence of a differential treat-ment response.
Onset of pain relief is faster with the5%lidocaine patch,opioid analgesics,and tramadol than with gaba-pentin or TCAs.This is primarily because gabapentin and TCAs require slower titration to effective dosages ow-ing to their adverse effects.Gabapentin,the5%lido-caine patch,and opioid analgesics all have fewer ad-verse drug interactions than tramadol or TCAs. Sequential and Combination Treatment With First-line Medications.The percentage of patients with neu-ropathic pain who do not respond to1of these5first-line medications but who then obtain satisfactory pain relief from a different one is unknown.Even within a class of medication,some patients fail to respond to one medi-cation but then respond to another.In a crossover trial comparing amitriptyline and nortriptyline in31pa-tients with PHN,5patients had moderate or severe pain when administered nortriptyline but none or mild pain with amitriptyline,and4patients had the opposite pat-tern of response.55Current understanding of the patho-physiologic mechanisms of neuropathic pain is consis-tent with the existence of multiple pain mechanisms,each of which may respond differently to medications with dif-ferent mechanisms of action.13-16Therefore,there is both an empiric and theoretical basis for recommending that patients who do not respond to1of these5first-line medi-cations be treated with another one.
It is common for patients to have a partial response to these medications,and combination treatment should be considered when this occurs.No studies have sys-tematically examined the efficacy of various possible com-binations of these5medications compared with mono-therapy.Despite the lack of controlled data,combinations of2or more of these first-line medications can be rec-ommended when patients have a partial response to a single one or at the beginning of treatment,either to in-crease the likelihood of a beneficial response or when a medication that requires titration to reach an effective dosage is also being used.Disadvantages of combina-tion therapy include an increased risk of adverse effects as the number of medications is increased and difficulty identifying which of several medications is responsible for the adverse effects.
Second-line Medications.When patients do not have a satisfactory response to treatment with the5first-line medications alone or in combination,several medica-tions can be considered second-line.Because these second-line treatments are used less often by physicians and fewer trials have examined their efficacy,their use is not de-scribed in detail.Recommendations for second-line medi-cations are based on positive results from a single ran-domized controlled trial or inconsistent results from multiple randomized controlled trials,with1excep-tion.
Other Anticonvulsant https://www.wendangku.net/doc/ac2409650.html,motrigine is the 1second-line pharmacologic treatment for which there is evidence of efficacy based on consistent results of mul-tiple randomized controlled trials for HIV sensory neu-ropathy,56,57PDN,58and central poststroke pain59as well as in a subgroup of patients with incomplete spinal cord lesions in a trial of patients with pain from spinal cord injury.60We do not consider lamotrigine a first-line treat-ment for neuropathic pain because of the slow and care-ful titration required and the risk of both severe rash and Stevens-Johnson syndrome associated with its use.
Carbamazepine has a well-established beneficial effect for trigeminal neuralgia24,30and is approved by the FDA for the treatment of this neuropathic pain syn-drome.In patients with PDN,some evidence exists for a beneficial effect of carbamazepine,but results from stud-ies of phenytoin are inconsistent;these clinical trials were conducted more than20years ago and do not meet cur-rent methodological standards.24,26-28On the basis of clini-cal trials of anticonvulsants for chronic neuropathic pain,
lamotrigine and carbamazepine can be recommended for patients who have not responded to an adequate trial of gabapentin when treatment with an anticonvulsant is sought.
Evaluation of the role of other second-generation an-ticonvulsants(eg,levetiracetam,oxcarbazepine,tiagab-ine,topiramate,and zonisamide)for the treatment of neu-ropathic pain must await publication of the results of randomized placebo-controlled trials.Although several anticonvulsant medications block sodium channels,avail-able anticonvulsants have different and often multiple mechanisms.Therefore,nonresponse to1anticonvul-sant does not necessarily predict nonresponse to the cat-egory as a whole.
Other Antidepressant Medications.Selective seroto-nin reuptake inhibitors have fewer adverse effects and are generally better tolerated than TCAs.In studies of pa-tients with PDN,paroxetine and citalopram were asso-ciated with statistically significantly greater pain relief than placebo,whereas fluoxetine hydrochloride was found to be no more effective than placebo.25-28Sustained-release bupropion hydrochloride was studied in a controlled trial of patients with different peripheral and central neuro-pathic pain syndromes and found to provide statisti-cally significant pain relief compared with placebo.61In a recent randomized,3-period crossover trial of venla-faxine hydrochloride and imipramine hydrochloride in patients with painful polyneuropathy,both antidepres-sants demonstrated superior pain relief compared with placebo but did not differ from each other.62A placebo-controlled crossover trial of13patients with chronic neu-ropathic pain following breast cancer surgery failed to find a significant benefit of venlafaxine vs placebo for the primary end point(daily pain diary ratings)but did find greater relief associated with venlafaxine treatment for 2secondary pain end points.63Results of these clinical trials indicate that bupropion,citalopram,paroxetine,and venlafaxine can be recommended for patients who have not responded to an adequate trial of nortriptyline(or another TCA)when additional treatment with an anti-depressant is being considered.
Beyond Second-line Medications.Other medications sometimes used for the treatment of patients with neu-ropathic pain include capsaicin,clonidine,dextrometh-orphan,and mexiletine.According to our clinical expe-rience and the inconsistent results of clinical trials,these medications may occasionally be effective in individual circumstances.
Future Needs
Treatment duration in most clinical trials of neuro-pathic pain has typically been8weeks or less;therefore, durability of pain relief and the long-term safety and tol-erability of treatment are unknown.With chronic dis-orders,it is important to consider the long-term cost-effectiveness of treatment.64Although the development of new treatments for neuropathic pain is continuing rap-idly,65,66few clinical trials have directly compared medi-cation options.45,55,62Such comparisons will make it pos-sible to determine not only whether treatments vary in their efficacy,safety,and tolerability but also,when con-ducted in the same patients,the extent to which treat-ment response with one medication predicts response to others.45Systematic evaluation of combination treat-ment is needed as well.Although a large percentage of patients with neuropathic pain are currently treated with 2or more of the first-and second-line medications dis-cussed,little is known about which patients are most likely to benefit from combination treatment and whether such treatment has additive or synergistic effects.Morever,be-cause combinations of pharmacologic and nonpharma-cologic treatments have received little study in patients with neuropathic pain,it is unknown,for example, whether physical therapy or psychological treatment pro-vides an additional benefit beyond that obtained from pharmacologic treatment alone.
CONCLUSIONS
Interest in the mechanisms and treatment of chronic neu-ropathic pain has increased during the past several years, and this is likely to result in significant treatment ad-vances in the future.These advances will make it pos-sible to go beyond the determination of whether treat-ment is effective to the identification of what treatments are most effective for which patients.13,67Progress in ba-sic science will lead to a greater understanding of the pathophysiologic mechanisms of neuropathic pain.Im-portant goals for clinical research are to devise methods for reliably identifying specific mechanisms in indi-vidual patients and to target treatment to them.13-17Greater attention should also be paid to developing preventive interventions for patients who are at risk for chronic neu-ropathic pain,including patients undergoing breast can-cer surgery,68those with herpes zoster,69and those with diabetes.70
Accepted for publication July24,2003.
From the Department of Anesthesiology,University of Rochester,Rochester,NY(Dr Dworkin);Department of Neu-rology,University of Wisconsin,Madison(Dr Backonja); Department of Neurology,University of California,San Fran-cisco(Dr Rowbotham);AstraZeneca,Wilmington,Del(Dr Allen);Department of Neurology,North Shore University Hospital,Manhasset,NY(Dr Argoff);Department of An-esthesiology,McGill University,Montreal,Quebec(Drs Ben-nett and Bushnell);Department of Neurology,University of Pennsylvania,Philadelphia(Dr Farrar);Endo Pharma-ceuticals,Chadds Ford,Pa(Dr Galer);Department of Psy-chiatry,Johns Hopkins University,Baltimore,Md(Dr Hay-thornthwaite);Ortho-McNeil Pharmaceutical,Raritan,NJ (Dr Hewitt);Departments of Neurosurgery(Dr Loeser)and Anesthesiology(Dr Turk),University of Washington,Se-attle;Pain and Neurosensory Mechanisms Branch,Na-tional Institute of Dental and Craniofacial Research,De-partment of Health and Human Services,Bethesda,Md(Dr Max);Pfizer,Groton,Conn(Dr Saltarelli);Department of Medicine and Geriatric Research,Education,and Clinical Center,Duke University and Durham VA Medical Cen-ters,Durham,NC(Dr Schmader);Department of Anesthe-siology,Freie Universita¨t Berlin,Berlin,Germany(Dr Stein); Innovus Research Inc,Medford,Mass(Dr Thompson);De-
partment of Anesthesiology,University of California,San Diego(Dr Wallace);Department of Psychology,Univer-sity of Colorado,Boulder(Dr Watkins);and Department of Anesthesiology,University of Utah,Salt Lake City(Dr Weinstein).
Author contributions:Study concept and design(Drs Dworkin,Backonja,Rowbotham,Allen,Argoff,Bush-nell,Farrar,Galer,Haythornthwaite,Hewitt,Loeser, Schmader,Stein,Thompson,Turk,Watkins,and Wein-stein);acquisition of data(Drs Dworkin,Rowbotham,Ar-goff,Bushnell,Max,and Saltarelli);analysis and inter-pretation of data(Drs Dworkin,Rowbotham,Allen,Argoff, Bennett,Farrar,Galer,Hewitt,Loeser,Max,Saltarelli, Stein,Wallace,and Weinstein);drafting of the manu-script(Drs Dworkin,Backonja,Rowbotham,Argoff,Ben-nett,Haythornthwaite,Hewitt,Max,Schmader,Stein,and Weinstein);critical revision of the manuscript for impor-tant intellectual content(Drs Dworkin,Backonja, Rowbotham,Allen,Argoff,Bennett,Bushnell,Farrar, Galer,Hewitt,Loeser,Max,Saltarelli,Schmader,Stein, Thompson,Turk,Wallace,Watkins,and Weinstein);sta-tistical expertise(Drs Dworkin,Bennett,Farrar,and Thompson);obtained funding(Drs Dworkin and Galer); administrative,technical,and material support(Drs Dwor-kin,Schmader,and Turk);study supervision(Dr Dworkin).
Dr Dworkin has received research support,consult-ing fees,or speakers bureau honoraria in the past year from Abbott Laboratories,Allergan,AstraZeneca,Bristol-Myers Squibb,Elan Pharmaceuticals,Eli Lilly and Co,Endo Pharmaceuticals,King Pharmaceuticals,Johnson and Johnson,NeurogesX,Novartis Pharmaceuticals,Ortho-McNeil Pharmaceutical,Pfizer,Purdue Pharma,Quigley Pharma,Reliant Pharmaceuticals,and UCB Pharma.Dr Rowbotham has been affiliated with or had financial in-volvement with Abbott Laboratories,Allergan,Bayer,Bio-gen,Blue Shield/United Behavioral Health,Elan,Endo Phar-maceuticals,Fulcrum Pharma,Gru¨nenthal GMBH,Hind Health Care,Lineberry Research Associates,NeuroMed Tech-nologies,Ortho-McNeil/Johnson and Johnson Pharmaceu-tical Research Institute,Pain Management Research LLC/ Teikoku Pharma USA,Pfizer,Schwarz Biosciences,and WinPharm Associates.Dr Farrar has received research or grant support from Pfizer,Cephalon,Smithkline Beecham, Knoll,and Searle;served as a consultant for Abbott Labo-ratories,Alza,Endo Pharmaceuticals,UCB Pharma,and Faulding;and served on the speakers bureau of Purdue Fre-derick.Dr Galer has been an employee of and has stock op-tions in Endo Pharmaceuticals and has received royalty pay-ments from Hind Health Care.Dr Max has participated in ongoing scientific collaborations or relevant discussions with Johnson and Johnson,Purdue Pharma,and Merck;has had employment conversations with Abbott Laboratories;and has served as a paid consultant for Pfizer,Abbott Laboratories, Endo Pharmaceuticals,AstraZeneca,Bristol-Myers Squibb, Eli Lilly,Bayer,Elan,Novartis,Watson Laboratories,and Wyeth-Ayerst.
Endo Pharmaceuticals provided an unrestricted edu-cational grant to the University of Rochester Office of Pro-fessional Education(Rochester,NY)to support a meeting on the treatment of neuropathic pain,and all authors ex-cept for Dr Max received an honorarium for participation in the meeting from the University of Rochester.
We thank William H.Bayer,MD,Kenneth R.Epstein, MD,Ronald M.Epstein,MD,Joseph M.Kovaz,MD,Bill H.McCarberg,MD,Gerald G.Ryan,MD,Thomas R.Tay-lor,MD,PhD,and Philip S.Whitecar,MD,for their thought-ful reviews of an initial draft of this article;Paul Lambiase and Mary Gleichauf of the University of Rochester Office of Professional Education for invaluable support;and Lili Dworkin for assistance with manuscript preparation.
Corresponding author and reprints:Robert H.Dwor-kin,PhD,Department of Anesthesiology,University of Roch-ester School of Medicine and Dentistry,601Elmwood Ave,Box604,Rochester,NY14642(e-mail: robert_dworkin@https://www.wendangku.net/doc/ac2409650.html,).
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