MANAGEMENT PERSPECTIVE For reprint orders, please contact: [email protected]
Best practices in the treatment of neuropathic pain
Practice Points
Dalia H Elmofty*1, Magdalena Anitescu1 & Asokumar Buvanendran2 Neuropathic pain can burden patients in multiple domains and remains a challenge to treat. The success in the treatment of neuropathic pain depends on evidence-based medicine and
individualized patient care. A multidisciplinary approach is suggested in the management of neuropathic pain. Preventative,
nonpharmacological, pharmacological and interventional options are recommended. Guidelines for the pharmacological management of neuropathic pain are available but limited for
interventional treatment options. Interventional treatment options are recommended in patients with refractory neuropathic pain.
SUMMARY Neuropathic pain is a complex pain syndrome that remains difficult to treat. Patients fail to obtain satisfactory relief despite receiving pharmacological agents. Neuro pathic pain has a significant impact on health-related quality of life. A multidisciplinary approach is recommended in the treatment of neuropathic pain. Preventative, nonpharmaco logical and pharmacological treatments are suggested in the management of neuropathic pain. Interventional options, such as spinal cord stimulation, intrathecal drug delivery, intra venous infusions therapies, and sympathetic nerve block, should be considered in patients with refractory neuropathic pain. Neuropathic pain is defined by the International Association for the Study of Pain as pain “caused by a lesion of the somatosensory nervous system” [1]. It is a chronic pain syndrome that can burden patients in multiple domains: socioeconomic, psychological and qualitative. Neuropathic pain has a negative impact on mental and physical health along with quality of life [2,3]. The health-related quality of life is lower in patients with neuropathic pain than in patients with chronic postneuropathic pain [4]. The management of chronic neuropathic pain continues to be a challenge for clinicians.
The use of evidence-based medicine in combination with individualizing treatment options is recommended. A patient’s comorbidities should be reviewed and considered when determining the plan of management. A multidisciplinary approach that utilizes preventative, pharmacological, nonpharmacological and interventional treatment options is preferred. Prevalence Population-based surveys have been used to identify the prevalence of neuropathic pain using the
Department of Anesthesia & Critical Care, University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637, USA Department of Anesthesiology, Rush University Medical Center, 1653 W Congress Parkway, Chicago, IL 60612, USA *Author for correspondence: Tel.: +1 773 702 6700; Fax: +1 773 834 218; [email protected] 1 2
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Management perspective Elmofty, Anitescu & Buvanendran Leeds Assessment of Neuropathic Symptoms and Signs score and the Douleur Neuropathique 4 questionnaires [5,6]. The Study of the Prevalence of Neuropathic Pain, a French population-based survey, estimated the prevalence of chronic pain with neuropathic characteristics to be 6.9% [5]. A similar study conducted in the UK reported a prevalence rate of 8.2% [6]. A Dutch study reported an annual incidence rate of 1% [7]. Neuropathic pain was more prevalent in females and increased with age. In a recent systematic review, it was estimated that one in five adults has chronic pain and one in 14 has neuropathic pain [8]. Pathophysiology Neuropathic pain is classified on the basis of the etiology of the lesion and location of insult in the nervous system. Neuropathic pain has many etiologies and can result from diabetes, herpes zoster virus, HIV, chemotherapy, or be induced by nerve trauma. The anatomical location of the lesion can be in the central or peripheral nervous system, or a mixed lesion. The broadness of this chronic pain syndrome and its coexistence with other types of pain makes the underlying mechanism of neuropathic pain relatively complex. Animal models of neuropathic pain have provided valuable information [9,10], and human pain research has also flourished in the past decade. A lesion in the afferent pathway predisposes to neuropathic pain [11]. Injury of neural tissue results in peripheral sensitization, an inflammatory response and a state of hyperexcitability in the primary afferent nociceptors. Prolonged afferent nociceptor input increases CNS hyperexcitability, known as c entral sensitization [12]. Diagnosis The assessment of pain is challenging because pain is subjective. The accuracy of measuring the experience of pain is undetermined. A thorough history and physical examination are fundamental in the investigation of pain. Neuropathic pain is characterized by a variety of symptoms ranging from a burning sensation to a shooting pain that may be persistent or paroxysmal in nature. Currently, there is a lack of a gold standard for confirming the presence of neuropathic pain. Standardized neuropathic pain screening tools (Leeds Assessment of Neuropathic Symptoms and Signs, Nonverbal Personality and Douleur Neuropathique 4 questionnaires, as well as Pain-Detect and ID Pain scales) have been developed to aid clinicians in
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the assessment of neuropathic pain [13]. Electrophysiological, quantitative sensory testing and punch biopsy of the skin (in cases of suspected small fiber neuropathy) can be useful for diagnostic evaluation [14]. It is important to identify the underlying etiology of neuropathic pain and the location of insult in the nervous system to prevent further damage and initiate appropriate treatment. Grading systems have been described to determine the likelihood that the source of pain is neuropathic. In a study that aimed to classify patients into one of three groups as definitely, possibly or unlikely to have neuropathic pain, there were few symptoms in patients with definite or possible neuropathic pain that differed from symptoms in patients unlikely to have neuropathic pain [15]. A grading system with four criteria has been described; pain distribution, link between history and pain distribution, clinical examination and diagnostic tests. However, the validity of this grading system is still to be determined [16]. A mechanism-based classification of neuropathic pain entails the selection of pharmacological agents based on the neurobiological mechanism of the pain state [17]. One of the obstacles with this approach is the inability to translate data obtained from animal studies of pain to the human model. Without fully understanding the mechanism of neuropathic pain in humans targeted pharmacological treatment may not be feasible. Treatment The physician–patient relationship is important in the management of chronic pain. Realistic goals, both from the physician and patient perspective, should be discussed. Measures to achieve the goals must be defined clearly and a multidisciplinary approach is recommended for the treatment of neuropathic pain. Preventative, nonpharmacological, pharmacological and interventional options should be considered. Prevention
Neuropathic pain is distressing and difficult to treat. Measures taken to prevent neuropathic pain caused by disease states are as important as its treatment. The Diabetes Control and Complication Trial and epidemiologic studies suggest that controlling blood sugar can prevent diabetic peripheral neuropathy in Type 1, with insufficent evidence for Type 2, diabetic
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Best practices in the treatment of n europathic pain patients [18]. Postherpetic neuralgia, similar to other types of neuropathic pain, is frequently refractory to treatment. In the USA, it is estimated that a million new cases of herpes zoster are diagnosed per year. Vaccination against herpes zoster virus may be an efficacious preventative measure. In the shingles prevention study, an investigational herpes zoster vaccine reduced morbidity from postherpetic neuralgia in the elderly population [19]. Amitriptyline was also beneficial in the prevention of postherpetic neuralgia [20]. Postsurgical neuropathic pain can be influenced by medications used preoperatively. Pre-emptive analgesia is beneficial in the prevention of postsurgical neuropathic pain by the inhibition of surgical-induced central sensitization. In a randomized, double-blinded trial, perioperative administration of pregablin reduced the incidence of chronic neuropathic knee pain after total knee arthroplasty [21]. It has also been demonstrated that venlafaxin (but not gabapentin) reduced the incidence of postsurgical mastectomy pain at 6 months [22]. Nonparmacological
Among the psychotherapeutic treatments for chronic pain are cognitive–behavioral therapy, biofeedback, hypnosis, operant–behavioral therapy and meditation. The goal of these therapies is to help the pain patient cope with their disease and improve function and quality of life [23]. Cognitive–behavioral therapy focuses on restructuring the negative emotions and behaviors into a goal-oriented and realistic approach in the management of pain. Operant–behavioral therapy focuses on the role family members play for pain management and discourages reinforcement of pain. Biofeedback teaches patients techniques to control physiological processes such as heart rate and muscle tone. Pharmacological
Cross-sectional studies of neuropathic pain have shown that even with pharmacological treatment, patients continue to experience moderate or severe pain [2]. The evidence-based literature shows that combination therapy has been more beneficial in the treatment of neuropathic pain than single agent therapy [24,25]. The superior efficacy of a two-drug combination was demonstrated in one review [26]. The authors recommend initiating medications at different time frames to determine efficacy and potential side effects. Caution should be taken
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Management perspective
with combination therapy to avoid drug interactions and additive effect on the side-effect profile. Common agents used in the treatment of neuropathic pain include antidepressants, anticonvulsants and opioids. Antidepressants
Tricyclic antidepressants (TCAs) were introduced in the 1950s as antipsychotics. TCAs were effective in numerous, randomized, blinded and placebo-controlled studies for the treatment of neuropathic pain. In a Cochrane review, TCAs were found to have a number needed-to-treat of approximately three [27]. The exact mechanism of action for the analgesic effect is still unclear. TCAs act primarily by inhibiting reuptake of norepinephrine and serotonin. They are also antagonistic at the N-methyl-d-aspartate receptor and may block sodium channels [28]. Their side effects include anticholinergic (altered mental status, dry mouth, mydriasis), CNS (myoclonus, syncope), cardiac (tachycardia, orthostatic hypotension), and gastrointestinal (decreased bowel motility) complications. Caution is necessary when TCAs are prescribed for the elderly or patients with cardiovascular comorbidities, an ECG is recommended before initiating therapy. There are two classes of TCAs, tertiary and secondary amines. The tertiary amines (amitriptyline) inhibit serotonin reuptake more than the secondary amines do. Tertiary amines have a tendency to cause sedation, anticholinergic-like side effects and orthostatic hypotension. A recent review suggests that amitriptyline may not be as efficacious in the treatment of neuropathic pain, specifically that associated with HIV or cancer [29]. Secondary amines (nortriptyline and desipramine) enhance inhibition of norepinephrine reuptake and have a more favorable side-effect profile than the tertiary amines, but these can cause irritability and disturbed sleep. Tertiary amines may be beneficial for patients with insomnia and secondary amines for patients with chronic fatigue. Serotonin- & norepinephrine-reuptake inhibitors
Serotonin- and norepinephrine-reuptake inhibitors (venlafaxin, milnacipran and duloxetine) exert balanced inhibition of reuptake of serotonin and norepinephrine that can be dose-dependent. Venlafaxin was effective in the treatment of neuropathic pain with similar needed-to-treat as TCAs [27]. Duloxetine 60 and 120 mg, but not 20 mg,
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Antidepressants (secondary amine TCAs, SNRIs) Anticonvulsants (gabapentin, pregabalin) Topical lidocaine
Antidepressants (TCAs) Anticonvulsants (gabapentin, pregabalin) Carbamazepine (first line only for trigeminal neuralgia) SNRIs (duloxetine, venlafaxine) Topical lidocaine Tramadol Extended release opioids
Antidepressants (TCAs, SNRIs) Anticonvulsants (gabapentin, pregablin)
Nonapplicable
Nonapplicable
Nonapplicable
Nonapplicable
DPN: Diabetic peripheral neuropathy; NMDA: N-methyl- d -aspartate; SNRI: Selective norepinephrine-reuptake inhibitors; TCA: Tricyclic antidepressant. Data taken from [39–41].
Nonapplicable
Carbamazepine and oxycarbezepine (if intolerable side effect, consider lamotrigine or surgical intervention)
Opioids Capsaicin cream
Antidepressants (TCAs) Anticonvulsant (gabapentin, pregablin) Topical lidocaine
Trigeminal neuralgia
Nonapplicable
Strong opioids
Tramadol
Antidepressants (TCAs) Anticonvulsants (gabapentin)
Central neuropathic pain
European Federation of Neurological Societies 2010 recommendations Painful Postherpetic polyneuropathy (DPN, neuralgia non-DPN)
Second-line Tramadol Tramadol treatment Opioids (oxycodone, methadone, morphine) Third-line NMDA antagonists Strong opioids treatment Topical capsaicin Mexiletine Other anticonvulsants (e.g., carbamezepine, lamotrigine, topirmate, valproic acid, oxycabazepine) Other antidepressants (e.g., bupropion, citalopram, paroxetine) Fourth-line Nonapplicable Cannabinoids Nonapplicable treatment Methadone Other anticonvulsants (topiramate, lamotrigine, valproic)
First-line treatment
Treatment Neuropathic Pain Specialists Canadian Pain Interest Group 2007 Society 2007 recommendations recommendations
Table 1. Pharmacological treatment of neuropathic pain: recommendations of the Neuropathic Pain Specialists Interest Group, the Canadian Pain Society and the European Federation of Neurological Societies.
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Best practices in the treatment of n europathic pain
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daily was effective in the treatment of diabetic peripheral neuropathy [30].
considered and discussed with the patient prior to initiation of treatment.
Selective serotonin-reuptake inhibitors
Neuropathic pain treatment guidelines The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, the Canadian Pain Society, and the European Federation of Neurological Societies have published evidence-based clinical guidelines for the pharmacological treatment of neuropathic pain (Table 1) [39–41]. The choice of the pharmacological agent for treatment depends on the potential benefit. In our practice with combination therapy, medications are introduced at separate time frames to determine efficacy and observe side effects. With a multimodal analgesic approach, different receptors can be targeted to maximize analgesia and minimize doses of
Selective serotonin-reuptake inhibitors (fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine) inhibit serotonin reuptake without affecting norepinephrine reuptake. These agents do not appear to be as efficacious as TCAs for the treatment of neuropathic pain [31,32]. Norepinephrine- & dopaminergic-reuptake inhibitors
Bupropion is a norepinephrine- and dopaminereuptake inhibitor. In a placebo-controlled crossover trial, bupropion sustained release was effective in the treatment of neuropathic pain [33]. Data on the use of norepinephrine and dopaminergic-reuptake inhibitors are limited. Anticonvulsants
Gabapentin and pregabalin are commonly used agents for the treatment of neuropathic pain. Both bind to the a-2-d subunit of the voltagegated calcium channel to reduce the release of excitatory neurotransmitters [34]. Their efficacy in the treatment of neuropathic pain has been demonstrated in randomized controlled trials [35,36]. Gabapentin was found to be effective in patients with neuropathic pain at doses of 1200 mg or more per day [37]. Opioids
The use of opioids for the treatment of neuropathic pain remains controversial. At our institution, opioids are administered to patients severely incapacitated from pain until antidepressant and anticonvulsant therapies are titrated to efficacy. Opioid agonists are also initiated if patients cannot tolerate antidepressant and/or anticonvulsant therapy. In a systematic review of randomized controlled trials of opioid agonists for the treatment of neuropathic nonmalignant pain, short-term trials (opioid administered less than 24 h) and intermediate-term trials (opioid administered 8–56 days) were identified. Results of short-term studies were equivocal; intermediate-term studies demonstrated significant efficacy for the treatment of neuropathic pain [38]. Opioids must be used cautiously. Careful monitoring and appropriate documentation is necessary for safe and effective use of opioids. The potential side effects of opioid therapy must be
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Box 1. Protocol for lidocaine infusion. Consultation Obtain baseline ECG and cardiac history Evaluate the patient for arrhythmias before scheduling procedure Day of procedure Assess the patient for fasting and alertness Determine effects of previous infusion, if any on: Pain reduction Duration of effects Patient function after infusion Decrease in use of pain medication since infusion Verify that patient has a companion to accompany them home Obtain signed consent Procedure Apply standard monitors: blood pressure, ECG, pulse oximeter and capnograph Start intravenous access and administer 1 mg/kg lidocaine bolus over 3–5 min Follow with 4 mg/kg lidocaine (or 2–4 mg) administered slowly over 30 min (or 20–30 min) Record at 1, 5, 10, 15, 20, 25 and 30 min the following: Time of administration Blood pressure Heart rate Pulse oximetry Pain score Stop the infusion in the event of seizure activity or cardiac instability Recovery Patients recover within 30–60 min after the procedure Vital signs are monitored over 15 min during recovery At the end of the recovery period, the patient is discharged from the clinic to the accompanying caregiver Follow-up In 4 weeks, patient returns for evaluation of treatment or repeat infusion The dose of lidocaine is not increased if the initial infusion was performed with 4 mg/kg over 20 min
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Management perspective Elmofty, Anitescu & Buvanendran Box 2. Protocol for ketamine infusion. Consultation Obtain baseline ECG and cardiac history Evaluate the patient for arrhythmias before scheduling procedure Day of procedure Assess the patient for fasting and alertness Determine effects of previous infusion, if any on: Pain reduction Duration of effects Patient function after infusion Decrease in use of pain medication since infusion Verify that patient has companion to accompany patient home Obtain signed consent Procedure Apply standard monitors: blood pressure, ECG, pulse oximeter and capnograph Start intravenous access and pretreat with: Midazolam 2 mg intravenously Ondansetron 4 mg intravenously Begin ketamine infusion with 0.3 mg/kg in 100 ml bag for 30–45 min At 1, 5, 10, 15, 20, 25 and 30 min record the following: Time of administration Blood pressure Heart rate Pulse oximetry Pain score Depending on the patient’s vital signs and pain scores, the infusion may be extended to 60 min Stop the infusion in the event of the following adverse effects: Hallucinations Blood pressure increase >20% of baseline Severe anxiety Nausea Unmanageable, symptomatic nystagmus Most adverse effects disappear when infusion is stopped Assess the patient for urgent management Recovery Patients recover within 30–60 min after the procedure Vital signs are monitored every 5–15 min during recovery At the end of the recovery period, the patient is discharged from the clinic to the accompanying caregiver Follow-up After 4 weeks patient returns for evaluation of treatment or repeat infusion Infusion doses may be increased to 0.6–1 mg/kg, depending on the effect of the infusion on pain scores and patient function or satisfaction with pain relief
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interventions should be performed by qualified specialists. Evidence-based data support the use of spinal cord stimulation [42], intrathecal drug delivery [43], intravenous infusion therapies [44,45] and sympathetic nerve blocks for the treatment of neuropathic pain. Interventional options should be used cautiously in clinical practice and reserved for patients that fail conventional therapy. Spinal cord stimulation
individual drugs, therefore reducing potential side effects.
The use of spinal cord stimulation can be an alternative treatment for certain types of neuropathic pain. It was first used in 1967 to treat neuropathic cancer pain [46]. In 2007, the European Federation of Neurological Societies proposed guidelines for the use of neurostimulation for neuropathic pain [42]. The mechanism of action of spinal cord stimulation still remains unclear. The gate control theory of pain proposed by Melzack and Wall provides some of the basic concepts behind simulation [47]. Spinal cord stimulation was effective for chronic pain associated with failed back surgery syndrome and complex regional pain syndrome [48]. Spinal cord stimulation was also beneficial for patients with painful diabetic polyneuropathy [49]. Cost–effectiveness studies have also favored spinal cord stimulation. In a randomized, controlled cross-over trial, cost–effectiveness of spinal cord stimulation or reoperation were compared in 42 patients with failed back surgery syndrome. Spinal cord stimulation was more cost effective than reoperation but was less effective after reoperation [50]. In the PROCESS study, spinal cord stimulation was associated with higher health costs at 6 months but improved health-related quality of life at 3 and 6 months compared with conventional medical management in patients with neuropathic pain from failed back surgery syndrome [51]. The 24-month follow-up study reported sustained improvement of health-related quality of life [52]. The EVIDENCE study will be the first multicenter, multinational, randomized controlled trial to assess the therapeutic effectiveness and cost–effectiveness of spinal cord stimulation versus reoperation in the treatment of failed back surgery syndrome [53]. Results of the study are currently unavailable.
Intervention
Intrathecal drug delivery
In spite of several guidelines, effective treatment for neuropathic pain remains undefinable. Complex pain syndromes may require treatment strategies that include interventional options. Such
The first administration of an intrathecal medication is credited to Leonard Corning in 1885 [54]. The identification of opioid receptors in the substantia gelatinosa of the dorsal horn of the
Pain Manage. (2013) 3(6)
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Best practices in the treatment of n europathic pain spinal cord led to the use of intrathecal opioid analgesia. Intrathecal treatment for neuropathic pain has been shown to be beneficial and should be considered when conservative measures have failed [43]. Opioids suitable for intrathecal administration include morphine, hydromorphone and fentanyl. The main advantage of intrathecal opioids is that the dose needed is lower than that for opioids taken orally, resulting in fewer adverse effects. One disadvantage is the formation of granulomas at the catheter tip, which can lead to spinal cord compression. Granuloma formation has been associated with escalating doses and concentrations of intrathecal opioids [55]. Intrathecal local anesthetics, however, such as bupivacaine, are effective in the treatment of neuropathic pain [56]. Dosage is adjusted to prevent numbness and weakness. Ziconotide, an intrathecally administered calcium channel blocker, has been beneficial in the treatment of refractory neuropathic pain [57]. Other agents that can be administered intrathecally include a-2 agoinsts (clonidine) and GABA agonists (baclofen). Dosing recommendations for intrathecal infusions were made at the o lyanalgesic consensus conference held in 2012 [58]. Intravenous infusion therapies
Intravenous lidocaine and ketamine infusions have been used in the treatment of neuropathic pain [44,45]. Lidocaine is a sodium channel blocker that is postulated to act centrally [59]. Ketamine is an N-methyl-d-aspartate receptor antagonist. N-methyl-d-aspartate receptor activation is associated with neuropathic pain [60]. Intravenous lidocaine infusions reduced neuropathic pain from spinal cord injury in a randomized, double-blinded crossover trial [59]. We showed sustained reduction of neuropathic pain from central sensitization in a number of pain conditions treated with intravenous lidocaine [61]. An initial bolus of lidocaine 1 mg/kg was administered followed by an infusion of 2–4 mg/kg over 30 min and a recovery period of 30 min–1 h. Patients were continuously monitored using American Society of Anesthesiologists recommended standard monitors (blood pressure, ECG, pulse oximetry, capnography), and pain scores were obtained by trained anesthesia personnel. Our protocol for outpatient lidocaine infusions is described in Box 1. Ketamine has been documented to be effective in patients with neuropathic pain [62–64]. It has also been used to treat cancer pain, postherpetic
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Management perspective
neuralgia and diabetic neuropathy [65]. The long-term side effects of ketamine are currently unknown. The short-term side effects include potential psychotomimetic or hemodynamic changes. In our pain clinic, patients who receive intravenous ketamine are pretreated with ondansetron and midazolam before slow administration of ketamine 0.3 mg/kg intravenously over 30–60 min and a recovery period of 30–90 min postinfusion. Patients are continuously monitored by trained anesthesia personnel for vital signs, pain and adverse effects during infusion and in the recovery period using American Society of Anesthesiologists standard monitors. Follow-up occurs 4 weeks following the infusion and depending on pain scores, the long-term effect of pain relief and the presence of adverse effects, the dose is increased, maintained or discontinued. Box 2 summarizes our protocol for outpatient ketamine infusion. Sympathetic nerve blocks
A dysfunction in the sympathetic nervous system occurs in certain types of neuropathic pain. Sympathetic blocks have been studied for the treatment of neuropathic pain [66]. At our institute, we incorporate sympathetic blocks as part of our diagnostic and treatment algorithm in selected cases of neuropathic pain. We conducted a retrospective analysis on the effectiveness of neurolytic celiac plexus blocks for severe upper abdominal cancer pain and found the duration of the pain relief lasted from 1 week to 4 months [67]. In terminal cancer patients, 1 week of pain relief may be considered a success if it resulted in an ease of suffering. Conclusion Neuropathic pain is a complex syndrome that remains difficult to treat and a multidisciplinary approach is recommended. Unfortunately, many of the treatment algorithms for neuropathic pain do not include interventional pain therapies. Additional randomized control trials are needed to support the role of interventional pain therapies in the management of neuropathic pain. Future perspective Interventional pain therapies, although currently not included in treatment algorithms, are beneficial in the treatment of refractory neuropathic pain. Reasonable evidence exists to support certain types of interventional pain therapies. To incorporate these therapies into treatment
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Management perspective Elmofty, Anitescu & Buvanendran algorithms, research studies comparing effectiveness are needed. We believe that in the next 5–10 years, such studies will be conducted. Financial & competing interest disclosure The authors have no relevant affiliations or financial involvement with any organizations or entity with a financial
References
10 Orstavik K, Weidner C, Schmidt R et al.
Pathological C-fibers in patients with a chronic painful condition. Brain 126, 567–578 (2003).
Papers of special note have been highlighted as: of interest of considerable interest n
n n
1
2
n
International Association for the Study of Pain. Pain terms, a current list with definitions and notes on usage. In: Classification of Chronic Pain (2nd Edition). Merskey H, Bogduk N (Eds). IASP Press, Seattle, WA, USA, 209–214 (1994). O’Connor A. Neuropathic pain. Quality-oflife impact, costs, and cost effectiveness of therapy. Pharmacoeconomics 27(2), 95–112 (2009). Provides insight on the detrimental effect neuropathic pain has on the quality of life.
3
Jensen MP, Chadroff MJ, Dworkins RH. The impact of neuropathic pain on health-related quality of life. Review and implications. Neurology 68, 1178–1182 (2007).
4
Smith B, Torrance N, Bennett M, Lee AJ. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin. J. Pain 23(2), 143–149 (2007).
5
6
7
8
9
482
interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
11 Baron R. Mechanisms of disease: neuropathic
pain – a clinical prospective. Nat. Clin. Prac. Neurol. 2, 95–106 (2006). 12 Curatolo M, Arendt-Nielsen L, Petersen-Felix
S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys. Med. Rehabil. Clin. N. Am. 17, 287–302 (2006). 13 Bennet MI, Attal N, Backonja MM et al.
Using screening tools to identify neuropathic pain. Pain 127, 199–203 (2007). 14 Cruccu G, Sommer C, Anand P et al. EFNS
guidelines on neuropathic pain assessment: revised 2009. Eur. J. Pain 17, 1010–1018 (2010). n n
Provides evidence-based guidelines on neuropathic pain assessment.
15 Rasmussen PV, Sindrup SH, Jensen TS, Bach
FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 10, 461–469 (2004).
Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380–387 (2008).
16 Treede RD, Jensen TS, Campbel JN et al.
Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominately neuropathic origin. Results from a general population survey. J. Pain 7, 281–289 (2006).
17 Finnerup NB, Jensen TS. Mechanisms of
Dieleman JP, Kerklaan J, Huygen F, Bouma P, Sturkenboom M. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 137, 681–688 (2008). Moore RA, Derry S, Taylor RS, Staube S, Phillips CJ. The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Pract. doi:10.1111/papr.12050 (2013) (Epub ahead of print). Sang CN, Gracely RH, Mas MB, Bennett GJ. Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories: evidence for a central mechanism. Anesthesiology 85, 491–496 (1996).
Neuropathic pain; redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635 (2008). disease: mechanism-based classification of neuropathic pain – a critical analysis. Nat. Clin. Pract. Neurol. 2(2), 107–115 (2006). 18 Boulton A, Vinik AI, Arezzo JC et al.
Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28(4), 956–962 (2005). 19 Oxman MN, Levin MJ. Vaccination against
herpes zoster and postherpetic neuralgia. J. Infect. Dis. 197(Suppl. 2), S228–S236 (2008). 20 Bowsher D. The effects of pre-emptive
treatment of post-herpetic neuralgia with amitriptyline: a randomized, double-blinded, placebo-controlled trial. J. Pain Symptom Manage. 13(6), 327–331 (1997). 21 Buvanendran A, Kroin J, Della Valle C, Kari
M, Moric M, Tuman K. Perioperative oral pregablin reduces chronic pain after total knee arthroplasty: a prospective, randomized,
Pain Manage. (2013) 3(6)
controlled trial. Anest. Analg. 110(1), 199–207 (2009). 22 Amr Y, Yousef A. Evaluation of the efficacy of
the perioperative administration of venlafaxin or gabapentin on acute or chronic post-mastectomy pain. Clin. J. Pain. 26 (5), 381–385 (2012). 23 Songer D. Psychotherapeutic approaches in
treatment of pain. Psychiatry 2(5), 19–24 (2005). 24 Gilron I, Bailey JM, Tu D, Holden RR, Weaver
DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N. Engl. J. Med. 352, 1324–1334 (2005). 25 Hanna M, O’Brien C, Wilson MC. Prolonged-
release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur. J. Pain. 12, 804–813 (2008). 26 Chaparro LE, Wiffen PJ, Moore RA, Gilron I.
Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst. Rev. 7, CD008943 (2012). 27 Saarto T, Wiffen PJ. Antidepressants for
neuropathic pain. Cochrane Database Syst. Rev. 4, CD005454 (2007). 28 Pancrazio JJ, Kamatchi GL, Roscoe AK,
Lynch C. Inhibition of neuronal Na+ channels by antidepressant drugs. J. Pharmacol. Exp. Therap. 284, 208–214 (1998). 29 Moore RA, Derry S, Aldington D, Cole P,
Wiffen PJ. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 12, CD008242 (2012). 30 Lunn MPT, Hughes RAC, Wiffen PJ.
Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst. Rev. 11, CD007115 (2011). 31 Finnerup NB, Otto M, Jensen TS, Sindrup
SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118, 289–305 (2005). 32 Max MB, Lynch SA, Muir J, Shoaf S, Smoller B,
Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N. Engl. J. Med. 326, 1250–1256 (1992). 33 Semenchuk MR, Sherman S, Davis B.
Double-blind, randomized trial of bupropion
future science group
Best practices in the treatment of n europathic pain SR for the treatment of neuropathic pain. Neurology 57, 1583–1588 (2001). 34 Dooley DJ, Taylor CP, Donevan S et al.
Ca 2+ channel a2-d ligands: novel modulators of neurotransmission. Trends Pharmacol. Sci. 28, 75–82 (2007). 35 Caraceni A, Zecca E, Bonezzi C et al.
Gabapentin for neuropathic cancer pain: a randomized controlled trial from the gabapentin cancer pain study group. J. Clin. Oncol. 22, 2909–2917 (2004). 36 Freynhagen R, Strojek K, Griesing T,
Wahlen E, Balkenohl M. Efficacy of pregablin in neuopathic pain evaluated in a 12-week, randomized, double-blind, multicenter, placebo-controlled trial of flexible-and fixed-dose regimens. Pain 115, 254–263 (2005). 37 Moore RA, Wiffen PJ, Derry S, McQuay HJ.
Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 3, CD007938 (2011). 38 Eisenberg E, McNicol ED, Carr DB. Efficacy
and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. Systematic review and meta-analysis of randomized controlled trials. JAMA 293(24), 3043–3052 (2005). 39 Dworkin RH, O’Connor AB, Backonja M
et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132, 237–251 (2007). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
40 Moulin DE, Clark AJ, Gilron I et al.
Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain. Res. Manage. 12(1), 13–21 (2007). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
41 Attal N, Cruccu G, Baron R et al.
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–1123 (2010). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
42 Cruccu G, Aziz TZ, Garcia-Larrea L et al.
EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur. J. Neurol. 14(9), 952–970 (2007). n n
Provides evidence-based recommendations for the use of neurostimulation in neuropathic pain.
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43 Jamison DE, Wilkinson IM, Cohen SP.
Intrathecal drug delivery for neuropathic pain. US Neurology 7(2), 154–162 (2011). 44 Park CH, Jung SH, Han CG. Effects of
intravenous lidocaine on the neuropathic pain of failed back surgery syndrome. Korean J. Pain 25(2), 94–98 (2012). 45 Kvarnstrom A, Karsten R, Quiding H,
Emanuelsson BM, Gordh T. The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain. Acta Anaesthesiol. Scand. 47, 868–878 (2003). 46 Shealy CN, Mortimer JT, Reswick JB.
Electrical inhibition of pain by simulation of the dorsal columns: preliminary clinical report. Anesth. Analg. 46(4), 489–491 (1997). 47 Melzack R, Wall PD. Pain mechanisms:
a theory. Science 150(699), 971–979 (1965). 48 Mailis-Gagnon A, Furlan AD, Sandoval JA
et al. Spinal cord stimulation for chronic pain. Cochrane Database Syst. Rev. 3, CD003783 (2004). 49 Pluijms W, Slangen R, Joosten E et al.
Electrical spinal cord stimulation in painful diabetic polyneuopathy, a systematic review on treatment efficacy and safety. Eur. J. Pain. 15, 783–788 (2011). 50 North R, Kidd D, Shipley J, Taylor R. Spinal
cord stimulation versus reoperation for failed back surgery syndrome: a cost effectiveness and cost utility analyses based on randomized control trial. Neurosurgery 61(2), 361–369 (2007). 51 Manca A, Kumar K, Taylor R et al. Quality of
life, resource consumption and cost of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial). Eur. J. Pain 12(8), 1047–1058 (2008). 52 Kumar K, Taylor R, Jacques L et al. The effects
of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery 63, 762–770 (2008). 53 North R, Kumar K, Wallace M. Spinal cord
stimulation versus reoperation in patients with failed back surgery syndrome: an international multicenter randomized controlled trial. Neuromodulation 14, 330–336 (2011). 54 Corning JL. Spinal anesthesia and local
medication of the cord. NY Med. J. 42, 483–485 (1885). 55 Gradert TL, Baze WB, Satterfield WC,
Hildebrand KR, Johansen MJ, Hassenbusch SJ. Safety of chronic intrathecal morphine infusion in a sheep model. Anesthesiology 99, 188–198 (2003).
Management perspective 56 Osenbach R. Intrathecal drug delivery in the
management of pain. In: Bonica’s Management of Pain (4th Edition). Fishman SM, Ballantyne JC, Pathmell JP, (Eds). Lippincott Williams and Wilkins, PA, USA, 1437–1458 (2010). 57 Rauck RL, Wallace MS, Burton AW, Kapural
L, North JM. Intrathecal ziconotide for neuropathic pain: a review. Pain 9(5), 327–337 (2009). 58 Deer TR, Prager J, Levy R et al. Polyanalgesic
consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 15(5), 436–466 (2012). 59 Finnerup N, Biering-Sorensen F, Johannesen
IL et al. Intravenouse lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 102, 1023–1030 (2005). 60 Petrenko AB, Yamakura T, Baba H et al.
The role of N-methyl-D-aspartate (NMDA) receptor in pain: a review. Anesth. Analg. 97, 25–28 (2003). 61 Fanaee E, Anitescu M, Patil SK. Sustained
pain relief after lidocaine infusions for chronic pain syndromes: A retrospective analysis. Presented at: American Society of Anesthesiologists Annual Meeting. Chicago, IL, USA, 16–20 October 2010. 62 Hocking G, Cousins MJ. Ketamine in
chronic pain management: an evidence-based review. Anesth. Analg. 97, 1730–1740 (2003). 63 Elsewaisy O, Slon B, Monagle J. Analgesic
effect of subanesthetic intravenous ketamine in refractory neuropatic pain: a case report. Pain Med. 11, 946–950 (2010). 64 Amr YM. Multi-day low dose ketamine
infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double-blinded trial. Pain Physician 13, 245–249 (2010). 65 Patil SK, Anitescu M. Efficacy of outpatient
ketamine infusions in refractory chronic pain syndromes: a 5 year retrospective analysis. Pain Med. 13, 263–269 (2012). 66 Straube S, Derry S, Moore RA, McQuay HJ.
Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome. Cochrane Database Syst. Rev. 7, CD002918 (2010). 67 Rupani G, Anitescu M. Celiac Plexus Block,
is it effective? A retrospective analysis for redefining the efficacy of neurolysis in metastatic cancer patients with severe upper abdominal pain. Presented at: American Society of Regional Anesthesia and Pain Medicine Fall Meeting. San Antonio, Texas, USA, 19–22 November 2009.
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Best practices in the treatment of neuropathic pain
Practice Points
Dalia H Elmofty*1, Magdalena Anitescu1 & Asokumar Buvanendran2 Neuropathic pain can burden patients in multiple domains and remains a challenge to treat. The success in the treatment of neuropathic pain depends on evidence-based medicine and
individualized patient care. A multidisciplinary approach is suggested in the management of neuropathic pain. Preventative,
nonpharmacological, pharmacological and interventional options are recommended. Guidelines for the pharmacological management of neuropathic pain are available but limited for
interventional treatment options. Interventional treatment options are recommended in patients with refractory neuropathic pain.
SUMMARY Neuropathic pain is a complex pain syndrome that remains difficult to treat. Patients fail to obtain satisfactory relief despite receiving pharmacological agents. Neuro pathic pain has a significant impact on health-related quality of life. A multidisciplinary approach is recommended in the treatment of neuropathic pain. Preventative, nonpharmaco logical and pharmacological treatments are suggested in the management of neuropathic pain. Interventional options, such as spinal cord stimulation, intrathecal drug delivery, intra venous infusions therapies, and sympathetic nerve block, should be considered in patients with refractory neuropathic pain. Neuropathic pain is defined by the International Association for the Study of Pain as pain “caused by a lesion of the somatosensory nervous system” [1]. It is a chronic pain syndrome that can burden patients in multiple domains: socioeconomic, psychological and qualitative. Neuropathic pain has a negative impact on mental and physical health along with quality of life [2,3]. The health-related quality of life is lower in patients with neuropathic pain than in patients with chronic postneuropathic pain [4]. The management of chronic neuropathic pain continues to be a challenge for clinicians.
The use of evidence-based medicine in combination with individualizing treatment options is recommended. A patient’s comorbidities should be reviewed and considered when determining the plan of management. A multidisciplinary approach that utilizes preventative, pharmacological, nonpharmacological and interventional treatment options is preferred. Prevalence Population-based surveys have been used to identify the prevalence of neuropathic pain using the
Department of Anesthesia & Critical Care, University of Chicago, 5841 S Maryland Avenue, Chicago, IL 60637, USA Department of Anesthesiology, Rush University Medical Center, 1653 W Congress Parkway, Chicago, IL 60612, USA *Author for correspondence: Tel.: +1 773 702 6700; Fax: +1 773 834 218; [email protected] 1 2
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Management perspective Elmofty, Anitescu & Buvanendran Leeds Assessment of Neuropathic Symptoms and Signs score and the Douleur Neuropathique 4 questionnaires [5,6]. The Study of the Prevalence of Neuropathic Pain, a French population-based survey, estimated the prevalence of chronic pain with neuropathic characteristics to be 6.9% [5]. A similar study conducted in the UK reported a prevalence rate of 8.2% [6]. A Dutch study reported an annual incidence rate of 1% [7]. Neuropathic pain was more prevalent in females and increased with age. In a recent systematic review, it was estimated that one in five adults has chronic pain and one in 14 has neuropathic pain [8]. Pathophysiology Neuropathic pain is classified on the basis of the etiology of the lesion and location of insult in the nervous system. Neuropathic pain has many etiologies and can result from diabetes, herpes zoster virus, HIV, chemotherapy, or be induced by nerve trauma. The anatomical location of the lesion can be in the central or peripheral nervous system, or a mixed lesion. The broadness of this chronic pain syndrome and its coexistence with other types of pain makes the underlying mechanism of neuropathic pain relatively complex. Animal models of neuropathic pain have provided valuable information [9,10], and human pain research has also flourished in the past decade. A lesion in the afferent pathway predisposes to neuropathic pain [11]. Injury of neural tissue results in peripheral sensitization, an inflammatory response and a state of hyperexcitability in the primary afferent nociceptors. Prolonged afferent nociceptor input increases CNS hyperexcitability, known as c entral sensitization [12]. Diagnosis The assessment of pain is challenging because pain is subjective. The accuracy of measuring the experience of pain is undetermined. A thorough history and physical examination are fundamental in the investigation of pain. Neuropathic pain is characterized by a variety of symptoms ranging from a burning sensation to a shooting pain that may be persistent or paroxysmal in nature. Currently, there is a lack of a gold standard for confirming the presence of neuropathic pain. Standardized neuropathic pain screening tools (Leeds Assessment of Neuropathic Symptoms and Signs, Nonverbal Personality and Douleur Neuropathique 4 questionnaires, as well as Pain-Detect and ID Pain scales) have been developed to aid clinicians in
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the assessment of neuropathic pain [13]. Electrophysiological, quantitative sensory testing and punch biopsy of the skin (in cases of suspected small fiber neuropathy) can be useful for diagnostic evaluation [14]. It is important to identify the underlying etiology of neuropathic pain and the location of insult in the nervous system to prevent further damage and initiate appropriate treatment. Grading systems have been described to determine the likelihood that the source of pain is neuropathic. In a study that aimed to classify patients into one of three groups as definitely, possibly or unlikely to have neuropathic pain, there were few symptoms in patients with definite or possible neuropathic pain that differed from symptoms in patients unlikely to have neuropathic pain [15]. A grading system with four criteria has been described; pain distribution, link between history and pain distribution, clinical examination and diagnostic tests. However, the validity of this grading system is still to be determined [16]. A mechanism-based classification of neuropathic pain entails the selection of pharmacological agents based on the neurobiological mechanism of the pain state [17]. One of the obstacles with this approach is the inability to translate data obtained from animal studies of pain to the human model. Without fully understanding the mechanism of neuropathic pain in humans targeted pharmacological treatment may not be feasible. Treatment The physician–patient relationship is important in the management of chronic pain. Realistic goals, both from the physician and patient perspective, should be discussed. Measures to achieve the goals must be defined clearly and a multidisciplinary approach is recommended for the treatment of neuropathic pain. Preventative, nonpharmacological, pharmacological and interventional options should be considered. Prevention
Neuropathic pain is distressing and difficult to treat. Measures taken to prevent neuropathic pain caused by disease states are as important as its treatment. The Diabetes Control and Complication Trial and epidemiologic studies suggest that controlling blood sugar can prevent diabetic peripheral neuropathy in Type 1, with insufficent evidence for Type 2, diabetic
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Best practices in the treatment of n europathic pain patients [18]. Postherpetic neuralgia, similar to other types of neuropathic pain, is frequently refractory to treatment. In the USA, it is estimated that a million new cases of herpes zoster are diagnosed per year. Vaccination against herpes zoster virus may be an efficacious preventative measure. In the shingles prevention study, an investigational herpes zoster vaccine reduced morbidity from postherpetic neuralgia in the elderly population [19]. Amitriptyline was also beneficial in the prevention of postherpetic neuralgia [20]. Postsurgical neuropathic pain can be influenced by medications used preoperatively. Pre-emptive analgesia is beneficial in the prevention of postsurgical neuropathic pain by the inhibition of surgical-induced central sensitization. In a randomized, double-blinded trial, perioperative administration of pregablin reduced the incidence of chronic neuropathic knee pain after total knee arthroplasty [21]. It has also been demonstrated that venlafaxin (but not gabapentin) reduced the incidence of postsurgical mastectomy pain at 6 months [22]. Nonparmacological
Among the psychotherapeutic treatments for chronic pain are cognitive–behavioral therapy, biofeedback, hypnosis, operant–behavioral therapy and meditation. The goal of these therapies is to help the pain patient cope with their disease and improve function and quality of life [23]. Cognitive–behavioral therapy focuses on restructuring the negative emotions and behaviors into a goal-oriented and realistic approach in the management of pain. Operant–behavioral therapy focuses on the role family members play for pain management and discourages reinforcement of pain. Biofeedback teaches patients techniques to control physiological processes such as heart rate and muscle tone. Pharmacological
Cross-sectional studies of neuropathic pain have shown that even with pharmacological treatment, patients continue to experience moderate or severe pain [2]. The evidence-based literature shows that combination therapy has been more beneficial in the treatment of neuropathic pain than single agent therapy [24,25]. The superior efficacy of a two-drug combination was demonstrated in one review [26]. The authors recommend initiating medications at different time frames to determine efficacy and potential side effects. Caution should be taken
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Management perspective
with combination therapy to avoid drug interactions and additive effect on the side-effect profile. Common agents used in the treatment of neuropathic pain include antidepressants, anticonvulsants and opioids. Antidepressants
Tricyclic antidepressants (TCAs) were introduced in the 1950s as antipsychotics. TCAs were effective in numerous, randomized, blinded and placebo-controlled studies for the treatment of neuropathic pain. In a Cochrane review, TCAs were found to have a number needed-to-treat of approximately three [27]. The exact mechanism of action for the analgesic effect is still unclear. TCAs act primarily by inhibiting reuptake of norepinephrine and serotonin. They are also antagonistic at the N-methyl-d-aspartate receptor and may block sodium channels [28]. Their side effects include anticholinergic (altered mental status, dry mouth, mydriasis), CNS (myoclonus, syncope), cardiac (tachycardia, orthostatic hypotension), and gastrointestinal (decreased bowel motility) complications. Caution is necessary when TCAs are prescribed for the elderly or patients with cardiovascular comorbidities, an ECG is recommended before initiating therapy. There are two classes of TCAs, tertiary and secondary amines. The tertiary amines (amitriptyline) inhibit serotonin reuptake more than the secondary amines do. Tertiary amines have a tendency to cause sedation, anticholinergic-like side effects and orthostatic hypotension. A recent review suggests that amitriptyline may not be as efficacious in the treatment of neuropathic pain, specifically that associated with HIV or cancer [29]. Secondary amines (nortriptyline and desipramine) enhance inhibition of norepinephrine reuptake and have a more favorable side-effect profile than the tertiary amines, but these can cause irritability and disturbed sleep. Tertiary amines may be beneficial for patients with insomnia and secondary amines for patients with chronic fatigue. Serotonin- & norepinephrine-reuptake inhibitors
Serotonin- and norepinephrine-reuptake inhibitors (venlafaxin, milnacipran and duloxetine) exert balanced inhibition of reuptake of serotonin and norepinephrine that can be dose-dependent. Venlafaxin was effective in the treatment of neuropathic pain with similar needed-to-treat as TCAs [27]. Duloxetine 60 and 120 mg, but not 20 mg,
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Antidepressants (secondary amine TCAs, SNRIs) Anticonvulsants (gabapentin, pregabalin) Topical lidocaine
Antidepressants (TCAs) Anticonvulsants (gabapentin, pregabalin) Carbamazepine (first line only for trigeminal neuralgia) SNRIs (duloxetine, venlafaxine) Topical lidocaine Tramadol Extended release opioids
Antidepressants (TCAs, SNRIs) Anticonvulsants (gabapentin, pregablin)
Nonapplicable
Nonapplicable
Nonapplicable
Nonapplicable
DPN: Diabetic peripheral neuropathy; NMDA: N-methyl- d -aspartate; SNRI: Selective norepinephrine-reuptake inhibitors; TCA: Tricyclic antidepressant. Data taken from [39–41].
Nonapplicable
Carbamazepine and oxycarbezepine (if intolerable side effect, consider lamotrigine or surgical intervention)
Opioids Capsaicin cream
Antidepressants (TCAs) Anticonvulsant (gabapentin, pregablin) Topical lidocaine
Trigeminal neuralgia
Nonapplicable
Strong opioids
Tramadol
Antidepressants (TCAs) Anticonvulsants (gabapentin)
Central neuropathic pain
European Federation of Neurological Societies 2010 recommendations Painful Postherpetic polyneuropathy (DPN, neuralgia non-DPN)
Second-line Tramadol Tramadol treatment Opioids (oxycodone, methadone, morphine) Third-line NMDA antagonists Strong opioids treatment Topical capsaicin Mexiletine Other anticonvulsants (e.g., carbamezepine, lamotrigine, topirmate, valproic acid, oxycabazepine) Other antidepressants (e.g., bupropion, citalopram, paroxetine) Fourth-line Nonapplicable Cannabinoids Nonapplicable treatment Methadone Other anticonvulsants (topiramate, lamotrigine, valproic)
First-line treatment
Treatment Neuropathic Pain Specialists Canadian Pain Interest Group 2007 Society 2007 recommendations recommendations
Table 1. Pharmacological treatment of neuropathic pain: recommendations of the Neuropathic Pain Specialists Interest Group, the Canadian Pain Society and the European Federation of Neurological Societies.
Management perspective Elmofty, Anitescu & Buvanendran
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Best practices in the treatment of n europathic pain
Management perspective
daily was effective in the treatment of diabetic peripheral neuropathy [30].
considered and discussed with the patient prior to initiation of treatment.
Selective serotonin-reuptake inhibitors
Neuropathic pain treatment guidelines The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, the Canadian Pain Society, and the European Federation of Neurological Societies have published evidence-based clinical guidelines for the pharmacological treatment of neuropathic pain (Table 1) [39–41]. The choice of the pharmacological agent for treatment depends on the potential benefit. In our practice with combination therapy, medications are introduced at separate time frames to determine efficacy and observe side effects. With a multimodal analgesic approach, different receptors can be targeted to maximize analgesia and minimize doses of
Selective serotonin-reuptake inhibitors (fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine) inhibit serotonin reuptake without affecting norepinephrine reuptake. These agents do not appear to be as efficacious as TCAs for the treatment of neuropathic pain [31,32]. Norepinephrine- & dopaminergic-reuptake inhibitors
Bupropion is a norepinephrine- and dopaminereuptake inhibitor. In a placebo-controlled crossover trial, bupropion sustained release was effective in the treatment of neuropathic pain [33]. Data on the use of norepinephrine and dopaminergic-reuptake inhibitors are limited. Anticonvulsants
Gabapentin and pregabalin are commonly used agents for the treatment of neuropathic pain. Both bind to the a-2-d subunit of the voltagegated calcium channel to reduce the release of excitatory neurotransmitters [34]. Their efficacy in the treatment of neuropathic pain has been demonstrated in randomized controlled trials [35,36]. Gabapentin was found to be effective in patients with neuropathic pain at doses of 1200 mg or more per day [37]. Opioids
The use of opioids for the treatment of neuropathic pain remains controversial. At our institution, opioids are administered to patients severely incapacitated from pain until antidepressant and anticonvulsant therapies are titrated to efficacy. Opioid agonists are also initiated if patients cannot tolerate antidepressant and/or anticonvulsant therapy. In a systematic review of randomized controlled trials of opioid agonists for the treatment of neuropathic nonmalignant pain, short-term trials (opioid administered less than 24 h) and intermediate-term trials (opioid administered 8–56 days) were identified. Results of short-term studies were equivocal; intermediate-term studies demonstrated significant efficacy for the treatment of neuropathic pain [38]. Opioids must be used cautiously. Careful monitoring and appropriate documentation is necessary for safe and effective use of opioids. The potential side effects of opioid therapy must be
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Box 1. Protocol for lidocaine infusion. Consultation Obtain baseline ECG and cardiac history Evaluate the patient for arrhythmias before scheduling procedure Day of procedure Assess the patient for fasting and alertness Determine effects of previous infusion, if any on: Pain reduction Duration of effects Patient function after infusion Decrease in use of pain medication since infusion Verify that patient has a companion to accompany them home Obtain signed consent Procedure Apply standard monitors: blood pressure, ECG, pulse oximeter and capnograph Start intravenous access and administer 1 mg/kg lidocaine bolus over 3–5 min Follow with 4 mg/kg lidocaine (or 2–4 mg) administered slowly over 30 min (or 20–30 min) Record at 1, 5, 10, 15, 20, 25 and 30 min the following: Time of administration Blood pressure Heart rate Pulse oximetry Pain score Stop the infusion in the event of seizure activity or cardiac instability Recovery Patients recover within 30–60 min after the procedure Vital signs are monitored over 15 min during recovery At the end of the recovery period, the patient is discharged from the clinic to the accompanying caregiver Follow-up In 4 weeks, patient returns for evaluation of treatment or repeat infusion The dose of lidocaine is not increased if the initial infusion was performed with 4 mg/kg over 20 min
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Management perspective Elmofty, Anitescu & Buvanendran Box 2. Protocol for ketamine infusion. Consultation Obtain baseline ECG and cardiac history Evaluate the patient for arrhythmias before scheduling procedure Day of procedure Assess the patient for fasting and alertness Determine effects of previous infusion, if any on: Pain reduction Duration of effects Patient function after infusion Decrease in use of pain medication since infusion Verify that patient has companion to accompany patient home Obtain signed consent Procedure Apply standard monitors: blood pressure, ECG, pulse oximeter and capnograph Start intravenous access and pretreat with: Midazolam 2 mg intravenously Ondansetron 4 mg intravenously Begin ketamine infusion with 0.3 mg/kg in 100 ml bag for 30–45 min At 1, 5, 10, 15, 20, 25 and 30 min record the following: Time of administration Blood pressure Heart rate Pulse oximetry Pain score Depending on the patient’s vital signs and pain scores, the infusion may be extended to 60 min Stop the infusion in the event of the following adverse effects: Hallucinations Blood pressure increase >20% of baseline Severe anxiety Nausea Unmanageable, symptomatic nystagmus Most adverse effects disappear when infusion is stopped Assess the patient for urgent management Recovery Patients recover within 30–60 min after the procedure Vital signs are monitored every 5–15 min during recovery At the end of the recovery period, the patient is discharged from the clinic to the accompanying caregiver Follow-up After 4 weeks patient returns for evaluation of treatment or repeat infusion Infusion doses may be increased to 0.6–1 mg/kg, depending on the effect of the infusion on pain scores and patient function or satisfaction with pain relief
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interventions should be performed by qualified specialists. Evidence-based data support the use of spinal cord stimulation [42], intrathecal drug delivery [43], intravenous infusion therapies [44,45] and sympathetic nerve blocks for the treatment of neuropathic pain. Interventional options should be used cautiously in clinical practice and reserved for patients that fail conventional therapy. Spinal cord stimulation
individual drugs, therefore reducing potential side effects.
The use of spinal cord stimulation can be an alternative treatment for certain types of neuropathic pain. It was first used in 1967 to treat neuropathic cancer pain [46]. In 2007, the European Federation of Neurological Societies proposed guidelines for the use of neurostimulation for neuropathic pain [42]. The mechanism of action of spinal cord stimulation still remains unclear. The gate control theory of pain proposed by Melzack and Wall provides some of the basic concepts behind simulation [47]. Spinal cord stimulation was effective for chronic pain associated with failed back surgery syndrome and complex regional pain syndrome [48]. Spinal cord stimulation was also beneficial for patients with painful diabetic polyneuropathy [49]. Cost–effectiveness studies have also favored spinal cord stimulation. In a randomized, controlled cross-over trial, cost–effectiveness of spinal cord stimulation or reoperation were compared in 42 patients with failed back surgery syndrome. Spinal cord stimulation was more cost effective than reoperation but was less effective after reoperation [50]. In the PROCESS study, spinal cord stimulation was associated with higher health costs at 6 months but improved health-related quality of life at 3 and 6 months compared with conventional medical management in patients with neuropathic pain from failed back surgery syndrome [51]. The 24-month follow-up study reported sustained improvement of health-related quality of life [52]. The EVIDENCE study will be the first multicenter, multinational, randomized controlled trial to assess the therapeutic effectiveness and cost–effectiveness of spinal cord stimulation versus reoperation in the treatment of failed back surgery syndrome [53]. Results of the study are currently unavailable.
Intervention
Intrathecal drug delivery
In spite of several guidelines, effective treatment for neuropathic pain remains undefinable. Complex pain syndromes may require treatment strategies that include interventional options. Such
The first administration of an intrathecal medication is credited to Leonard Corning in 1885 [54]. The identification of opioid receptors in the substantia gelatinosa of the dorsal horn of the
Pain Manage. (2013) 3(6)
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Best practices in the treatment of n europathic pain spinal cord led to the use of intrathecal opioid analgesia. Intrathecal treatment for neuropathic pain has been shown to be beneficial and should be considered when conservative measures have failed [43]. Opioids suitable for intrathecal administration include morphine, hydromorphone and fentanyl. The main advantage of intrathecal opioids is that the dose needed is lower than that for opioids taken orally, resulting in fewer adverse effects. One disadvantage is the formation of granulomas at the catheter tip, which can lead to spinal cord compression. Granuloma formation has been associated with escalating doses and concentrations of intrathecal opioids [55]. Intrathecal local anesthetics, however, such as bupivacaine, are effective in the treatment of neuropathic pain [56]. Dosage is adjusted to prevent numbness and weakness. Ziconotide, an intrathecally administered calcium channel blocker, has been beneficial in the treatment of refractory neuropathic pain [57]. Other agents that can be administered intrathecally include a-2 agoinsts (clonidine) and GABA agonists (baclofen). Dosing recommendations for intrathecal infusions were made at the o lyanalgesic consensus conference held in 2012 [58]. Intravenous infusion therapies
Intravenous lidocaine and ketamine infusions have been used in the treatment of neuropathic pain [44,45]. Lidocaine is a sodium channel blocker that is postulated to act centrally [59]. Ketamine is an N-methyl-d-aspartate receptor antagonist. N-methyl-d-aspartate receptor activation is associated with neuropathic pain [60]. Intravenous lidocaine infusions reduced neuropathic pain from spinal cord injury in a randomized, double-blinded crossover trial [59]. We showed sustained reduction of neuropathic pain from central sensitization in a number of pain conditions treated with intravenous lidocaine [61]. An initial bolus of lidocaine 1 mg/kg was administered followed by an infusion of 2–4 mg/kg over 30 min and a recovery period of 30 min–1 h. Patients were continuously monitored using American Society of Anesthesiologists recommended standard monitors (blood pressure, ECG, pulse oximetry, capnography), and pain scores were obtained by trained anesthesia personnel. Our protocol for outpatient lidocaine infusions is described in Box 1. Ketamine has been documented to be effective in patients with neuropathic pain [62–64]. It has also been used to treat cancer pain, postherpetic
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Management perspective
neuralgia and diabetic neuropathy [65]. The long-term side effects of ketamine are currently unknown. The short-term side effects include potential psychotomimetic or hemodynamic changes. In our pain clinic, patients who receive intravenous ketamine are pretreated with ondansetron and midazolam before slow administration of ketamine 0.3 mg/kg intravenously over 30–60 min and a recovery period of 30–90 min postinfusion. Patients are continuously monitored by trained anesthesia personnel for vital signs, pain and adverse effects during infusion and in the recovery period using American Society of Anesthesiologists standard monitors. Follow-up occurs 4 weeks following the infusion and depending on pain scores, the long-term effect of pain relief and the presence of adverse effects, the dose is increased, maintained or discontinued. Box 2 summarizes our protocol for outpatient ketamine infusion. Sympathetic nerve blocks
A dysfunction in the sympathetic nervous system occurs in certain types of neuropathic pain. Sympathetic blocks have been studied for the treatment of neuropathic pain [66]. At our institute, we incorporate sympathetic blocks as part of our diagnostic and treatment algorithm in selected cases of neuropathic pain. We conducted a retrospective analysis on the effectiveness of neurolytic celiac plexus blocks for severe upper abdominal cancer pain and found the duration of the pain relief lasted from 1 week to 4 months [67]. In terminal cancer patients, 1 week of pain relief may be considered a success if it resulted in an ease of suffering. Conclusion Neuropathic pain is a complex syndrome that remains difficult to treat and a multidisciplinary approach is recommended. Unfortunately, many of the treatment algorithms for neuropathic pain do not include interventional pain therapies. Additional randomized control trials are needed to support the role of interventional pain therapies in the management of neuropathic pain. Future perspective Interventional pain therapies, although currently not included in treatment algorithms, are beneficial in the treatment of refractory neuropathic pain. Reasonable evidence exists to support certain types of interventional pain therapies. To incorporate these therapies into treatment
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Management perspective Elmofty, Anitescu & Buvanendran algorithms, research studies comparing effectiveness are needed. We believe that in the next 5–10 years, such studies will be conducted. Financial & competing interest disclosure The authors have no relevant affiliations or financial involvement with any organizations or entity with a financial
References
10 Orstavik K, Weidner C, Schmidt R et al.
Pathological C-fibers in patients with a chronic painful condition. Brain 126, 567–578 (2003).
Papers of special note have been highlighted as: of interest of considerable interest n
n n
1
2
n
International Association for the Study of Pain. Pain terms, a current list with definitions and notes on usage. In: Classification of Chronic Pain (2nd Edition). Merskey H, Bogduk N (Eds). IASP Press, Seattle, WA, USA, 209–214 (1994). O’Connor A. Neuropathic pain. Quality-oflife impact, costs, and cost effectiveness of therapy. Pharmacoeconomics 27(2), 95–112 (2009). Provides insight on the detrimental effect neuropathic pain has on the quality of life.
3
Jensen MP, Chadroff MJ, Dworkins RH. The impact of neuropathic pain on health-related quality of life. Review and implications. Neurology 68, 1178–1182 (2007).
4
Smith B, Torrance N, Bennett M, Lee AJ. Health and quality of life associated with chronic pain of predominantly neuropathic origin in the community. Clin. J. Pain 23(2), 143–149 (2007).
5
6
7
8
9
482
interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
11 Baron R. Mechanisms of disease: neuropathic
pain – a clinical prospective. Nat. Clin. Prac. Neurol. 2, 95–106 (2006). 12 Curatolo M, Arendt-Nielsen L, Petersen-Felix
S. Central hypersensitivity in chronic pain: mechanisms and clinical implications. Phys. Med. Rehabil. Clin. N. Am. 17, 287–302 (2006). 13 Bennet MI, Attal N, Backonja MM et al.
Using screening tools to identify neuropathic pain. Pain 127, 199–203 (2007). 14 Cruccu G, Sommer C, Anand P et al. EFNS
guidelines on neuropathic pain assessment: revised 2009. Eur. J. Pain 17, 1010–1018 (2010). n n
Provides evidence-based guidelines on neuropathic pain assessment.
15 Rasmussen PV, Sindrup SH, Jensen TS, Bach
FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 10, 461–469 (2004).
Bouhassira D, Lanteri-Minet M, Attal N, Laurent B, Touboul C. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain 136, 380–387 (2008).
16 Treede RD, Jensen TS, Campbel JN et al.
Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominately neuropathic origin. Results from a general population survey. J. Pain 7, 281–289 (2006).
17 Finnerup NB, Jensen TS. Mechanisms of
Dieleman JP, Kerklaan J, Huygen F, Bouma P, Sturkenboom M. Incidence rates and treatment of neuropathic pain conditions in the general population. Pain 137, 681–688 (2008). Moore RA, Derry S, Taylor RS, Staube S, Phillips CJ. The costs and consequences of adequately managed chronic non-cancer pain and chronic neuropathic pain. Pain Pract. doi:10.1111/papr.12050 (2013) (Epub ahead of print). Sang CN, Gracely RH, Mas MB, Bennett GJ. Capsaicin-evoked mechanical allodynia and hyperalgesia cross nerve territories: evidence for a central mechanism. Anesthesiology 85, 491–496 (1996).
Neuropathic pain; redefinition and a grading system for clinical and research purposes. Neurology 70, 1630–1635 (2008). disease: mechanism-based classification of neuropathic pain – a critical analysis. Nat. Clin. Pract. Neurol. 2(2), 107–115 (2006). 18 Boulton A, Vinik AI, Arezzo JC et al.
Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care 28(4), 956–962 (2005). 19 Oxman MN, Levin MJ. Vaccination against
herpes zoster and postherpetic neuralgia. J. Infect. Dis. 197(Suppl. 2), S228–S236 (2008). 20 Bowsher D. The effects of pre-emptive
treatment of post-herpetic neuralgia with amitriptyline: a randomized, double-blinded, placebo-controlled trial. J. Pain Symptom Manage. 13(6), 327–331 (1997). 21 Buvanendran A, Kroin J, Della Valle C, Kari
M, Moric M, Tuman K. Perioperative oral pregablin reduces chronic pain after total knee arthroplasty: a prospective, randomized,
Pain Manage. (2013) 3(6)
controlled trial. Anest. Analg. 110(1), 199–207 (2009). 22 Amr Y, Yousef A. Evaluation of the efficacy of
the perioperative administration of venlafaxin or gabapentin on acute or chronic post-mastectomy pain. Clin. J. Pain. 26 (5), 381–385 (2012). 23 Songer D. Psychotherapeutic approaches in
treatment of pain. Psychiatry 2(5), 19–24 (2005). 24 Gilron I, Bailey JM, Tu D, Holden RR, Weaver
DF, Houlden RL. Morphine, gabapentin, or their combination for neuropathic pain. N. Engl. J. Med. 352, 1324–1334 (2005). 25 Hanna M, O’Brien C, Wilson MC. Prolonged-
release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. Eur. J. Pain. 12, 804–813 (2008). 26 Chaparro LE, Wiffen PJ, Moore RA, Gilron I.
Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst. Rev. 7, CD008943 (2012). 27 Saarto T, Wiffen PJ. Antidepressants for
neuropathic pain. Cochrane Database Syst. Rev. 4, CD005454 (2007). 28 Pancrazio JJ, Kamatchi GL, Roscoe AK,
Lynch C. Inhibition of neuronal Na+ channels by antidepressant drugs. J. Pharmacol. Exp. Therap. 284, 208–214 (1998). 29 Moore RA, Derry S, Aldington D, Cole P,
Wiffen PJ. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 12, CD008242 (2012). 30 Lunn MPT, Hughes RAC, Wiffen PJ.
Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst. Rev. 11, CD007115 (2011). 31 Finnerup NB, Otto M, Jensen TS, Sindrup
SH. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain 118, 289–305 (2005). 32 Max MB, Lynch SA, Muir J, Shoaf S, Smoller B,
Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N. Engl. J. Med. 326, 1250–1256 (1992). 33 Semenchuk MR, Sherman S, Davis B.
Double-blind, randomized trial of bupropion
future science group
Best practices in the treatment of n europathic pain SR for the treatment of neuropathic pain. Neurology 57, 1583–1588 (2001). 34 Dooley DJ, Taylor CP, Donevan S et al.
Ca 2+ channel a2-d ligands: novel modulators of neurotransmission. Trends Pharmacol. Sci. 28, 75–82 (2007). 35 Caraceni A, Zecca E, Bonezzi C et al.
Gabapentin for neuropathic cancer pain: a randomized controlled trial from the gabapentin cancer pain study group. J. Clin. Oncol. 22, 2909–2917 (2004). 36 Freynhagen R, Strojek K, Griesing T,
Wahlen E, Balkenohl M. Efficacy of pregablin in neuopathic pain evaluated in a 12-week, randomized, double-blind, multicenter, placebo-controlled trial of flexible-and fixed-dose regimens. Pain 115, 254–263 (2005). 37 Moore RA, Wiffen PJ, Derry S, McQuay HJ.
Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst. Rev. 3, CD007938 (2011). 38 Eisenberg E, McNicol ED, Carr DB. Efficacy
and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin. Systematic review and meta-analysis of randomized controlled trials. JAMA 293(24), 3043–3052 (2005). 39 Dworkin RH, O’Connor AB, Backonja M
et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132, 237–251 (2007). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
40 Moulin DE, Clark AJ, Gilron I et al.
Pharmacological management of chronic neuropathic pain-consensus statement and guidelines from the Canadian Pain Society. Pain. Res. Manage. 12(1), 13–21 (2007). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
41 Attal N, Cruccu G, Baron R et al.
EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur. J. Neurol. 17, 1113–1123 (2010). n n
Provides evidence-based recommendations for the pharmacological treatment of neuropathic pain.
42 Cruccu G, Aziz TZ, Garcia-Larrea L et al.
EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur. J. Neurol. 14(9), 952–970 (2007). n n
Provides evidence-based recommendations for the use of neurostimulation in neuropathic pain.
future science group
43 Jamison DE, Wilkinson IM, Cohen SP.
Intrathecal drug delivery for neuropathic pain. US Neurology 7(2), 154–162 (2011). 44 Park CH, Jung SH, Han CG. Effects of
intravenous lidocaine on the neuropathic pain of failed back surgery syndrome. Korean J. Pain 25(2), 94–98 (2012). 45 Kvarnstrom A, Karsten R, Quiding H,
Emanuelsson BM, Gordh T. The effectiveness of intravenous ketamine and lidocaine on peripheral neuropathic pain. Acta Anaesthesiol. Scand. 47, 868–878 (2003). 46 Shealy CN, Mortimer JT, Reswick JB.
Electrical inhibition of pain by simulation of the dorsal columns: preliminary clinical report. Anesth. Analg. 46(4), 489–491 (1997). 47 Melzack R, Wall PD. Pain mechanisms:
a theory. Science 150(699), 971–979 (1965). 48 Mailis-Gagnon A, Furlan AD, Sandoval JA
et al. Spinal cord stimulation for chronic pain. Cochrane Database Syst. Rev. 3, CD003783 (2004). 49 Pluijms W, Slangen R, Joosten E et al.
Electrical spinal cord stimulation in painful diabetic polyneuopathy, a systematic review on treatment efficacy and safety. Eur. J. Pain. 15, 783–788 (2011). 50 North R, Kidd D, Shipley J, Taylor R. Spinal
cord stimulation versus reoperation for failed back surgery syndrome: a cost effectiveness and cost utility analyses based on randomized control trial. Neurosurgery 61(2), 361–369 (2007). 51 Manca A, Kumar K, Taylor R et al. Quality of
life, resource consumption and cost of spinal cord stimulation versus conventional medical management in neuropathic pain patients with failed back surgery syndrome (PROCESS trial). Eur. J. Pain 12(8), 1047–1058 (2008). 52 Kumar K, Taylor R, Jacques L et al. The effects
of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery 63, 762–770 (2008). 53 North R, Kumar K, Wallace M. Spinal cord
stimulation versus reoperation in patients with failed back surgery syndrome: an international multicenter randomized controlled trial. Neuromodulation 14, 330–336 (2011). 54 Corning JL. Spinal anesthesia and local
medication of the cord. NY Med. J. 42, 483–485 (1885). 55 Gradert TL, Baze WB, Satterfield WC,
Hildebrand KR, Johansen MJ, Hassenbusch SJ. Safety of chronic intrathecal morphine infusion in a sheep model. Anesthesiology 99, 188–198 (2003).
Management perspective 56 Osenbach R. Intrathecal drug delivery in the
management of pain. In: Bonica’s Management of Pain (4th Edition). Fishman SM, Ballantyne JC, Pathmell JP, (Eds). Lippincott Williams and Wilkins, PA, USA, 1437–1458 (2010). 57 Rauck RL, Wallace MS, Burton AW, Kapural
L, North JM. Intrathecal ziconotide for neuropathic pain: a review. Pain 9(5), 327–337 (2009). 58 Deer TR, Prager J, Levy R et al. Polyanalgesic
consensus conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation 15(5), 436–466 (2012). 59 Finnerup N, Biering-Sorensen F, Johannesen
IL et al. Intravenouse lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 102, 1023–1030 (2005). 60 Petrenko AB, Yamakura T, Baba H et al.
The role of N-methyl-D-aspartate (NMDA) receptor in pain: a review. Anesth. Analg. 97, 25–28 (2003). 61 Fanaee E, Anitescu M, Patil SK. Sustained
pain relief after lidocaine infusions for chronic pain syndromes: A retrospective analysis. Presented at: American Society of Anesthesiologists Annual Meeting. Chicago, IL, USA, 16–20 October 2010. 62 Hocking G, Cousins MJ. Ketamine in
chronic pain management: an evidence-based review. Anesth. Analg. 97, 1730–1740 (2003). 63 Elsewaisy O, Slon B, Monagle J. Analgesic
effect of subanesthetic intravenous ketamine in refractory neuropatic pain: a case report. Pain Med. 11, 946–950 (2010). 64 Amr YM. Multi-day low dose ketamine
infusion as adjuvant to oral gabapentin in spinal cord injury related chronic pain: a prospective, randomized, double-blinded trial. Pain Physician 13, 245–249 (2010). 65 Patil SK, Anitescu M. Efficacy of outpatient
ketamine infusions in refractory chronic pain syndromes: a 5 year retrospective analysis. Pain Med. 13, 263–269 (2012). 66 Straube S, Derry S, Moore RA, McQuay HJ.
Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome. Cochrane Database Syst. Rev. 7, CD002918 (2010). 67 Rupani G, Anitescu M. Celiac Plexus Block,
is it effective? A retrospective analysis for redefining the efficacy of neurolysis in metastatic cancer patients with severe upper abdominal pain. Presented at: American Society of Regional Anesthesia and Pain Medicine Fall Meeting. San Antonio, Texas, USA, 19–22 November 2009.
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