Treatment of Neuropathic Pain Disorder: A Review of Recent Studies

Neuropathic Pain:  A Review of Recent Publications
by Wise Young, PhD MD
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, 604 Allison Rd, Piscataway, NJ 08852-8082
15 December 2008

Neuropathic pain or pain that originates from the central nervous system, as opposed to pain that arise from noxious sensory input, afflicts millions of people after injuries to the nervous system.  Here is a review of recent studies of neuropathic pain and its treatment in human in 2008.

Neuropathic Pain in Germany. Berger, et al. [1] studied 275,685 adults with painful neuropathic disorder (PND) in Germany.  These patients are more likely (47% versus 20% of age- and sex-matched controls) to have co-morbidities, such as circulatory disorders, depression, and anxiety.  They are also more likely to have received pain medications (57% vs. 13% of controls).  They expressed the concern that these patients are not being optimally treated.  It is quite impressive to me that these authors were able to find a database of over 275,000 patients with PND.  Given that Germany has a population of 82 million, this suggests an incidence of >3354 case/million.

Pregabalin Treatment of PND.  In a separate study, Berger, et al. [2] looked for Pregabalin use in patient with PND that were 18 or older between 2004 and 2006.  They found 1400 patients in UK that started pregabalin therapy.  Most had received at 3 or more drugs before starting pregabalin.  After starting the drug, they averaged 4 prescriptions, totaling 93 therapy days.  The patients took fewer other pain drugs once they started pregabalin, including tricyclic antidepressants (16% versus 37% before), opioids (55% versus 64% before), and anti-epileptic drugs other than pregabalin (16% vs. 36% before).  Pregabalin seems to be associated with reduced concomitant use of other pain drugs.

Painful Diabetic Neuropathy.  O’Connor, et al. [3] compared the costs for four drug therapies (desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day, and duloxetine 60 mg/day) for pain diabetic neuropathy.  They used a controversial method called quality adjusted life year (QALY) to measure the cost-effectiveness of the treatment.  Desipramine and duloxetine were both more effective and less expensive than gabapentin and pregabalin.  As I understand the study results, based on clinical trial data of efficacy and the cot of the drug, desipramine had the best effect with the least cost.  Desipramine is a tricyclic antidepressant drug.  Jones, et al. [4] found the chronic administration of desipramine significantly attenuated mechanical allodynia in rats with selective spinal nerve ligation.  Desipramine treated rats showed significantly greater activation of multiple brain sites than sham-operated and saline control rats.

Memantine profoundly reduced pain.  Hackworth, et al. [5] gave memantine to two patients iwth severe phantom limb pain.  Memantine is the first of a novel calss of anti-Alzheimer drugs that blocks NMDA glutamate receptors.  It is a old drug, having been patented in 1968 by Eli Lilly.  Both patients were refractory to high dose opioids and adjunctive pain medications and were receiving large doses of oral methadone, intravenous hydromorphone, tricyclic anti-depressants, anti-inflammatory and anti-epileptic drugs.  Both patients had profound relief from their pain without any apparent side effects from the drug. Yamamoto, et al. [6] and others have shown that NMDA receptors contribute to neuropathic pain and ketamine (a long used NMDA receptor blocker) has been used to treat cancer pain.

Effect of tricyclic antidepressants on neutrophils.  Tricyclic anti-depressants (TCA) are amongst the most commonly used medications for depression and neuropathic pain.  Ploppa, et al. [7] studied the effects of amitriptyline, nortriptyline, and fluoxetine on neutrophils (the white blood cells that are responsible for killing bacteria in blood).  At concentrations of 0.10 mM , none of the the compounds had any effect on neutrophil phagocytosis.  However, at 1 mM concentration, all three compounds were highly toxic to neutrophils.  Amitriptyline didn’t kill the cells but stopped their function while nortriptyline and fluoxetine caused “marked disruption of neutrophils”.  This particular side effect of TCA is a hard limiting factor on the dose of these drugs.

Effect of amitriptyline on stomach emptying.  In healthy volunteers, Bouras, et al. [8] showed that 25 mg of amitriptyline slowed down gastric emptying at 2 and 4 hours without affect gastric volumes or satiation volume.  It reduced nausea scores at 30 minutes after a high calorie liquid load.  These findings suggest a basis for the long-term use of TCA drugs to treat chronic somatic and gastrointestinal pain disorders, including refractory dyspepsia.  Given that people with spinal cord injury have slower gastric emptying anyway, this suggests that perhaps the best time to take amitriptyline may be several hours after a meal.

A case for opioid therapy of neuropathic pain.  Allen [9] made a plea for rationale multiple drug therapy of neuropathic pain, pointing out that opioids will never replace tricyclic antidepressants and anti-epileptic drugs as the first line therapy for neuropathic pain but that opioids are now full established as effective second- and third-line therapies.  In 2006, Dobecki, et al. [9] pointed out that neuropathic pain is a very common condition, affecting nearly 1.5% of the U.S. population.  The US FDA has approved five medications for neuropathic pain, including gabapentin, pregabalin, duloxetine, 5% lidocaine patch, and carbamazepine.  Other agents with proven efficacy in multiple randomized placebo-controlled trials include opioids, tricyclic antidepressants, venlafaxine, and tramadol.  All the these agents have been recommended as first-line therapies for neuropathic pain.  So, the field has moved in the last few years, from a budding recognition that some drugs may work for neuropathic pain to formal acknowledgment that they are first-line therapies.

In summary, neuropathic pain is a very common and unsolved problem.  In Germany, one study alone identified over a quarter million people who have neuropathic and suggested that this population is not being adequately cared for.  A study of Pregabalin treatment suggest that it is often given after patients have tried other treatments but it significantly reduced the concomitant use of other pain medications.  A comparison of desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day, and duloxetine suggested that the tricyclic antidepressant desipramine had the best effective and was the least costly.  One study reported that memantine, an NMDA receptor blocker, remarkably reduced severe phantom limb pain in two patients who had become refractory to all other drugs.  Several studies provided some insight into why tricyclic antidepressant drugs are toxic and how amitriptyline may slow gastric emptying.  Finally, the field of central pain management is beginning to understand and accept the use of opioid therapies for neuropathic pain.

References

  1. Berger A, Toelle T, Sadosky A, Dukes E, Edelsberg J and Oster G (2008).  Clinical and Economic Characteristics of Patients with Painful Neuropathic Disorders in Germany.  Pain Pract.   Policy Analysis Inc. (PAI), Brookline, Massachusetts, U.S.A. blacksquare, square, filled Abstract: Using a large database with information from general practitioners (GP) throughout Germany, we identified all adults (age >/=18 years) with encounters for painful neuropathic disorders (PNDs) between August 1, 2005 and July 31, 2006 (PND patients). We also constituted an age- and sex-matched comparison group, consisting of randomly selected patients without any GP encounters for PNDs during the same period. Selected characteristics were then compared between PND patients and those in the comparison group over the 1-year study period. The study sample consisted of 275,685 PND patients and a similar number in the matched comparison group; mean age was 53.7 years, and 57% were women. PND patients were more likely than matched comparators to have encounters for various comorbidities, including circulatory system disorders (47% vs. 20%, respectively), depression (9% vs. 2%), and anxiety (4% vs. 1%) (all P < 0.01). They also were more likely to have received pain-related medications (57% vs. 13% for comparison group; P < 0.01)-most commonly, nonsteroidal anti-inflammatory drugs, benzodiazepines, and opioids, and less often, tricyclic antidepressants and anti-epileptics. PND patients averaged 7.3 more GP visits during the year (mean [95% CI] = 9.9 [9.9, 9.9] vs. 2.6 [2.6, 2.7] for comparison group); they also had significantly more specialist referrals and physician-excused absences from work (all P < 0.01). Patients with PNDs under the care of GPs in Germany have comparatively more comorbidities and higher levels of use of healthcare services. The pain-related medications that these patients receive raise concerns that PNDs may not be optimally treated in these settings. blacksquare, square, filled.
  2. Berger A, Sadosky A, Dukes E, Edelsberg J and Oster G (2008).  Use of Pregabalin in Patients with Painful Neuropathic Disorders under the Care of General Practitioners in the U.K.  Pain Pract.   Policy Analysis Inc. (PAI), Brookline, Massachusetts, U.S.A. Purpose: To examine the use of pregabalin in patients with painful neuropathic disorders under the care of general practitioners (GPs) in the U.K. Materials and Methods: Using a large U.K. database of GP encounters, we identified all persons aged >/= 18 years with at least one GP encounter with a diagnosis of a painful neuropathic disorder (eg, postherpetic neuralgia, diabetic peripheral neuropathy) between January 1, 2004 and July 31, 2006. Among these patients, we then identified those who initiated therapy with pregabalin; the date of initial receipt of pregabalin was designated the “index date.” We then examined use of pregabalin over the 6-month period following this date (“follow-up”), as well as changes in the use of other pain-related medications (eg, opioids, tricyclic antidepressants [TCAs], other antiepileptics [AEDs]) between the 6-month period preceding the index date (“pretreatment”) and follow-up. Patients with less than 6 months of pretreatment and follow-up data were excluded, as were those without any encounters during pretreatment for a painful neuropathic disorder. Results: A total of 1,400 patients (1.4% of all identified patients with painful neuropathic disorders) initiated therapy with pregabalin and met all other entry criteria; mean age was 62 years, and 58% were women. During pretreatment, most (54%) patients received three or more different types of pain-related medications. During follow-up, patients averaged four prescriptions for pregabalin, totaling 93 therapy days. Compared with pretreatment, fewer patients received other pain-related medications during follow-up, including TCAs (37% during pretreatment vs. 27% during follow-up), opioids (64% vs. 55%), and AEDs other than pregabalin (36% vs. 16%) (all P < 0.01). Conclusions: In the U.K., many patients prescribed pregabalin by their GPs may have been refractory to other pain-related medications. Use of these medications declined following initiation of pregabalin therapy.
  3. O’Connor AB, Noyes K and Holloway RG (2008).  A cost-utility comparison of four first-line medications in painful diabetic neuropathy.  Pharmacoeconomics.  26: 1045-64.  Department of Medicine, University of Rochester School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA. BACKGROUND: Painful diabetic neuropathy is common and adversely affects patients’ quality of life and function. Several treatment options exist, but their relative efficacy and value are unknown. OBJECTIVE: To determine the relative efficacy, costs and cost effectiveness of the first-line treatment options for painful diabetic neuropathy. METHODS: Published and unpublished clinical trial and cross-sectional data were incorporated into a decision analytic model to estimate the net health and cost consequences of treatment for painful diabetic peripheral neuropathy over 3-month (base case), 1-month and 6-month timeframes. Efficacy was measured in QALYs, and costs were measured in $US, year 2006 values, using a US third-party payer perspective.The patients included in the model were outpatients with moderate to severe pain associated with diabetic peripheral neuropathy and no contraindications to treatment with tricyclic antidepressants. Four medications were compared: desipramine 100 mg/day, gabapentin 2400 mg/day, pregabalin 300 mg/day and duloxetine 60 mg/day. RESULTS: Desipramine and duloxetine were both more effective and less expensive than gabapentin and pregabalin in the base-case analysis and through a wide range of sensitivity analyses. Duloxetine offered borderline value compared with desipramine in the base case ($US47 700 per QALY), but not when incorporating baseline-observation-carried-forward analyses of the clinical trial data ($US867 000 per QALY). The results were also sensitive to the probability of obtaining pain relief with duloxetine. CONCLUSIONS: Desipramine (100 mg/day) and duloxetine (60 mg/day) appear to be more cost effective than gabapentin or pregabalin for treating painful diabetic neuropathy. The estimated value of duloxetine relative to desipramine depends on the assumptions made in the statistical analyses of clinical trial data.
  4. Jones KL, Finn DP, Governo RJ, Prior MJ, Morris PG, Kendall DA, Marsden CA and Chapman V (2008).  Identification of discrete sites of action of chronic treatment with desipramine in a model of neuropathic pain.  Neuropharmacology.   Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Nottingham NG7 2UH, UK. Tricyclic antidepressants (TCAs) are an important analgesic treatment for neuropathic pain, though the neural substrates mediating these effects are poorly understood. We have used an integrative approach combining behavioural pharmacology with functional magnetic resonance imaging (fMRI) to investigate the effects of chronic treatment with the TCA desipramine, on touch-evoked pain (mechanical allodynia) and brain regional activity in the selective spinal nerve ligation (SNL) model of neuropathic pain. SNL and sham-operated rats received once daily i.p. administration of 10 mg/kg DMI, or saline, for 14 days. Withdrawal responses to the application of a normally non-noxious (10 g) stimulus were recorded in SNL and sham-operated rats over this period. On the final day of the study, SNL and sham-operated rats received a final challenge dose of DMI (10 mg/kg i.p.) during fMRI scanning. Chronic administration of desipramine (DMI) significantly attenuated mechancial allodynia in SNL rats. DMI challenge in chronic DMI-treated neuropathic rats produced significantly greater activation of the deep mesencephalic nucleus, primary somatosensory cortex, insular cortex, medial globus pallidus, inferior colliculus, perirhinal cortex and cerebellum compared to sham-operated rats and saline controls. By contrast, the spatial pattern of brain regional activation by chronic DMI treatment in sham controls encompassed a number of other areas including those associated with learning and memory processes. These novel findings identify key brain regions implicated in the analgesic and mood altering effects associated with chronic treatment with DMI.
  5. Hackworth RJ, Tokarz KA, Fowler IM, Wallace SC and Stedje-Larsen ET (2008).  Profound pain reduction after induction of memantine treatment in two patients with severe phantom limb pain.  Anesth Analg.  107: 1377-9.  Naval Medical Center San Diego, Department of Anesthesiology, 34800 Bob Wilson Drive, San Diego, CA 92134, USA. We present the cases of two patients who suffered severe lower extremity injuries and subsequently developed phantom limb pain (PLP) that was refractory to high dose opioids and adjunctive pain medications. Both patients were receiving large doses of oral methadone, IV hydromorphone via a patient-controlled analgesia delivery system, and adjunctive medications including tricyclic antidepressants, nonsteroidal anti-inflammatory medications, and anti-epileptics. Despite these treatments, the patients had severe PLP. Upon induction of the oral N-methyl-D-aspartate receptor antagonist memantine, both patients had a profound reduction in their PLP without any apparent side effects from the medication.
  6. Yamamoto T (2008).  [Mechanisms of the development of neuropathic pain and its treatment].  Nihon Hansenbyo Gakkai Zasshi.  77: 215-8.  Department of Anesthesiology, Kumamoto University Hospital, 1-1-1 Honjo, Kumamoto-shi, Kumamoto 860-8556, Japan. yamamoto@fc.kh.kumamoto-u.ac.jp. Neuropathic pain has been known to be refractory to traditional analgesics, such as opioids and non-steroidal anti-inflammatoy drugs. Some mechanisms of the development of neuropathic pain have been proposed; 1) sprouting of A beta fibers to the superficial layer of the dorsal horn, 2) ectopic discharge in the dorsal root ganglion and/or in neuroma at the nerve stump, 3) spinal sensitization. Ectopic discharge has been reported to be inhibited by Na+ channel blocker, such as lidocaine, and anticonvulsant. Lidocaine and anticonvulsant are used in the management of neuropathic pain. Activation of NMDA receptor is usually involved in the development of spinal sensitization and NMDA receptor antagonist, such as ketamine, is used in the management of neuropathic pain. Recently, alpha2delta subunit blocker, new class of anticonvulsant, is introduced to the management of neuropathic pain. alpha2delta subunit is the subunit of Ca2+ channel and modulate the influx of Ca2+. This Ca2+ influx induces release of neurotransmitter in the neuron. alpha 2 delta subunit blockers, such as gabapentin and pregabalin, may reduce the release of neurotransmitter and elicit analgesic effect in the treatment of neuropathic pain.
  7. Ploppa A, Ayers DM, Johannes T, Unertl KE and Durieux ME (2008).  The inhibition of human neutrophil phagocytosis and oxidative burst by tricyclic antidepressants.  Anesth Analg.  107: 1229-35.  Department of Anesthesiology and Intensive Care Medicine, Eberhard-Karls University Tuebingen, Hoppe-Seyler-Str. 3, 72 076 Tuebingen, Germany. annette.ploppa@uni-tuebingen.de. BACKGROUND: Tricyclic antidepressants are being investigated as long-acting analgesics for topical application in wounds or IV for postoperative pain relief. However, it remains unclear if tricyclic antidepressants affect the host defense and if reported toxic effects on neutrophils are of relevance in this setting. We therefore investigated the effects of amitriptyline, nortriptyline, and fluoxetine on human neutrophil phagocytosis, oxidative burst, and neutrophil toxicity in a human whole blood model. METHODS: Heparinized blood samples from healthy volunteers were incubated with amitriptyline, nortriptyline, or fluoxetine (10(-6) to 10(-3) M) for 0, 1, or 3 h. Staphylococcus aureus in a bacteria:neutrophil ratio of 5:1 and dihydroethidium (for the determination of oxidative burst) were added. Phagocytosis was stopped after 5, 10, 20, and 40 min. After lysis of red blood cells, samples were analyzed by flow cytometry. RESULTS: In concentrations up to 10(-4) M, none of the compounds affected neutrophil phagocytosis and oxidative burst. At 10(-3) M, all three compounds were highly toxic for neutrophils. Amitriptyline preserved morphological integrity, but completely suppressed neutrophil function. Nortriptyline and fluoxetine caused a marked disruption of neutrophils. The effects of the investigated antidepressants were not time-dependent. CONCLUSIONS: Phagocytosis and intracellular host defense are largely unaffected by antidepressants in concentrations of 10(-4) M and below. Our results confirm that antidepressants are highly toxic to neutrophils in millimolar concentrations. The neurotoxic effects and clinical side effects, but not effects on neutrophil functions, therefore, are likely to be the limiting factors in using antidepressants as analgesics.
  8. Bouras EP, Talley NJ, Camilleri M, Burton DD, Heckman MG, Crook JE and Richelson E (2008).  Effects of amitriptyline on gastric sensorimotor function and postprandial symptoms in healthy individuals: a randomized, double-blind, placebo-controlled trial.  Am J Gastroenterol.  103: 2043-50.  Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida 32211, USA. BACKGROUND: Low-dose tricyclic antidepressants have been used to treat chronic somatic and gastrointestinal pain disorders, including refractory functional dyspepsia. However, there are only limited data on the effects of these drugs on upper gastrointestinal function. AIM: To compare the effects of two doses of amitriptyline (AMT) and placebo on gastric accommodation, emptying, satiation, and postprandial symptoms in healthy volunteers. METHODS: Using a parallel-group, double-blind, placebo-controlled design, 41 healthy volunteers were randomized to AMT 25 mg, AMT 50 mg, or placebo for 2 wk. During the final 3 days of therapy, the following end points were assessed: fasting and postprandial gastric volumes, 2- and 4-h gastric emptying, time and volume to maximum satiation using a nutrient drink test, and postprandial symptoms 30 min later using 10-cm visual analog scales. AMT and metabolite levels were measured. RESULTS: AMT slowed gastric emptying at 2 h (median 75% for placebo, 57% for AMT 25 mg, 67% for AMT 50 mg; P= 0.037) and 4 h (median 98% for placebo, 96% for AMT 25 mg, 92% for AMT 50 mg; P= 0.003). AMT did not affect gastric volumes or satiation volume, but it did reduce nausea scores at 30 min in a dose-dependent manner (median 2.1 for placebo, 0.9 for AMT 25 mg, and 0.0 for AMT 50 mg; P= 0.009). CONCLUSION: In healthy volunteers, AMT slows gastric emptying of solids, but it does not significantly affect gastric volumes or satiation. AMT reduces nausea after challenge with a high calorie liquid load.
  9. Allen SC (2008).  Neuropathic pain – the case for opioid therapy.  Oncology.  74 Suppl 1: 76-82.  Royal Berkshire Hospital, Reading, UK. stephenallen@lineone.net. For many patients, neuropathic pain (NeP) is arguably more difficult to control than nociceptive or ‘normal’ pain. We also now recognise the great burden that NeP has on the lives of patients – it is not only a matter of treating pain in isolation, but managing all of the issues that affect the patient’s quality of life. Until relatively recently we have had little understanding of the pathophysiology causing NeP and have relied on the secondary effects of non-analgesic drugs as the mainstays of treatment. Greater understanding of the pathophysiology of NeP has led to more appropriate therapy and an increased use of multiple drug therapy – ‘rational polypharmacy’. Traditional opinions concerning the treatment of NeP have been challenged and it is because of this that the use of opioids in NeP has been re-evaluated. Opioids will never replace tricyclic antidepressants and anti-epileptic drugs as first-line therapy for NeP. However, they are now fully established as effective and useful second- or third-line drugs. Many patients in the past have been potentially undertreated as a result of our inertia to use opioids. The case for opioid therapy in NeP has been firmly established.
  10. Dobecki DA, Schocket SM and Wallace MS (2006).  Update on pharmacotherapy guidelines for the treatment of neuropathic pain.  Curr Pain Headache Rep.  10: 185-90.  Center for Pain and Palliative Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Neuropathic pain is a common problem in our society affecting nearly 1.5% of the US population. There currently are five medications approved by the US Food and Drug Administration (FDA) for the treatment of neuropathic pain, which include gabapentin, pregabalin, duloxetine, 5% lidocaine patch, and carbamazepine. Other agents with proven efficacy in multiple randomized, placebo-controlled trials include opioids, tricyclic antidepressants, venlafaxine, and tramadol. All of these agents, both FDA-approved and off-label, have been recommended as first-line treatments for neuropathic pain. This article discusses these agents in detail as they relate to the treatment of neuropathic pain.
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