Wise Young, PhD MD

Many people take tricyclic antidepressant drugs for neuropathic pain and for depression. They are called tricyclic antidepressant (TCA) because they are small molecules with three rings.  The original tricyclic antidepressant was imipramine.  There are many members of the drug family including amitriptyline (also called Elavil, Endep, Tryptanol, Tripiline, Amyzol) , desipramine (norpramin, pertograne), doxepin (Adapin, Sinequan), nortriptyline (Aventyl, Pamelor, Noritren), and many others.  In this article, I will review their use, mechanism, toxicity, and withdrawal.

Mechanisms of Action

The mechanism of tricyclic antidepressants are not well understood until recently. They are believed to block the re-uptake of neurotransmitters norepinephrine and serotonin by neurons but not dopamine.  They may also bind to muscarinic and histamine H1 receptors.  While the pharmacological effects can be see immediately, anti-depressive effects are typically not seen for several weeks.

When neurons release catecholaminergic neurotransmitters (e.g. serotonin, norepinephrine), the length of time that they act depends on the speed with which they are broken down (by monoamine oxidase) and are taken up the neurons (re-uptake).  A family of proteins called biogenic amine transporters take up catecholaminergic neurotransmitters.

Tricyclic antidepressants bind to biogenic amine transporters, interfering with re-uptake of neurotransmitters.  Thus, they are like the serotonin uptake blockers except that they are less selective.   It is possible that they may have other mechanisms of action at lower doses.

Treatment for Depression

In 2004, Moncrieff, et al. [1] did a Cochrane Review of 9 studies from 1990-2000, involving 751 participants and comparing TCA drugs.  Combining all the studies showed consistent and significant effects of antidepressant drugs.  One the trials was strongly positive, skewing the other results.  If this trial were removed, this reduced the effect. Conservative analyses suggest small differences and a large placebo effect.

In 2007, Bramness, et al. [2] assessed the relationship between antidepressant sales and suicide rates in Norway.  Sales of non-tricyclic antidepressants (non-TCA) and suicides were clearly negatively related, i.e. increased sales of the non-TCA was associated with decreases of suicide.  Mottram, et al. [3] examined elderly patients and found that TCA compared less favorably due to high withdrawal rate from side-effects.

In 2008, Nieuwenhuijsen, et al. [4] did a Cochrane Review of 2556 participants in randomized clinical trials examining interventions in depressed workers.  They found no evidence of an effect of medication alone, enhanced primary care, psychological interventions, or combinations of these.

Treatment for Neuropathic Pain

In 2007, Saarto & Wiffen [5] updated a 2005 Cochrane Review, reviewing antiepressant drugs on neuropathic pain.  The review included  61 trials of 20 antidepressants (3293 participants) and concluded that  TCA drugs provided significant but moderate pain relief.  There was limited evidence for efficacy of selective serotonin uptake blockers.  One of three patients given a TCA drug or venlafaxine achieved moderate pain relief.

In 2006, the European Federation of Neurological Societies [6] reviewed clinical trial evidence and concluded that there was level A evidence for efficacy of TCA, gabapentin, pregabalin, and opioids for neuropathic pain.  This was followed by topical lidocaine for post-herpetic syndrome and venlafaxine and duloxetine for diabetic neuropathy.

In 2005, Namaka, et al. [7] proposed a treatment algorithm whereby the first-line therapies included tricyclic antidepressants, anti-epileptic drugs, topical anti-neuralgics, and analgesics.  If the patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried.  Patients that do not respond to monotherapy may respond to combinations.  This is now widely accepted.

Toxicity of TCA

Because TCA is the lowest cost first-line therapy, they are tried in almost all patients with depression and neuropathic pain.  From this perspective, it is paramount that the toxicity and interaction of the drug with other drugs be considered in planning treatment programs.  There are many contraindications for TCA use.

1. Monoamine oxidase (MAO) use.  Nortriptyline should not be used in concurrently with a monoamine oxidase (MAO) because it can cause high body temperatures (hyperpyretic crisis), severe convulsions, and fatalities.  All MAO inhibitors should be discontinued at least two weeks for Nortriptyline is started. Some MAO drugs include isoarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate).
2. Patients that are hypersensitive to dibenzazepine may also be allergic to nortriptyline.
3. Myocardial infarction.  Nortiptyline should not be given during the acute recovery period after MI.
4. Alcohol consumption.  Alcohol potentiates the effects of nortriptyline and may lead to increased suicide attempts or overdoses.
5. Schizophrenia.  Patients with schizophrenia may have an exacerbation of their psychosis or nortriptyline may
6. Manic depression.  Nortriptyline may cause symptoms of the manic phase to emerge, as well as patient hostility and epilepiform seizures.
7. Anti-cholinergic and sympathomimetic drugs.  Close supervision is required when nortriptyline is used with anti-cholinegic and sympathomimetic drugs.
8. Suicide.  If a depressed patient has a history of suicide, it is important that the least possible quantity of drug be dispensed at any given time because depressed patients often take high doses of tricyclic antidepressants for suicide.
9. Diabetes.  Both elevation and lowering of blood surgar levels have been reported with nortriptyline.

The major difference between TCA use in depression and neuropathic pain is dose.  For example, the typical doses of amitriptyline used for depression and neuropathic pain are 125 mg/day and 25 mg/day respectively.  Rintala, et al. [8] found that amitriptyline (25-50 mg/day) was significantly better than placebo or gabapentin for relieving chronic neuropathic pain in persons with spinal cord. At the doses, side effects should be less.

Drug Interactions and Adverse Reactions

Tricyclic antidepressants enhances the effects of many drugs because it interferes with neurotransmitter uptake.  However, some drugs interfere with metabolism of tricyclic antidepressants.

• Cimetidine increases plasma concentrations of tricyclic antidepressants.
• Chlorporamide (250 mg/day) and nortriptyline (125 mg/day) may be associated with significant hypoglycemia in a patient with type II diabetes.
• Amitriptyline enhances the effects of alcohol and other CNS depressants.
• Amitriptyline and disulfiram may cause delirium.

Common side-effects include drowsiness, dizziness, insomnia, blurred vision, rash, and dry moth.  High doses of tricyclic antidepressants have the following adverse reactions:

• Cardiovascular:  hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, and stroke.
• Psychiatric:  confusion states with hallucination, disorientation, delusions, anxiety, restlessness, agitation, insomnia, panic, nightmares, hypomania, exacerbation of psychosis.
• Neurologic:  numbness and tingling (paresthesias) of the limbs, discoodination, ataxia, tremors, peripheral neuropathy, extrapyramidal symptoms, seizures, EEG alterations, and tinnitus
• Anticholinergic:  Dry mouth, sublingual adenitis, blurred vision, changes in accomodation, mydriasis, constipation, paralytic ileus, urinary retention, delayed micturition (urination).
• Allergy.  skin rash, petechiae, urticaria, photosensitization, edema (face and tongue), drug fever, cross-sensitivity to related drugs.
• Hematologic.  Bone marrow depression, agranulocytosis, eosinophilia, purpura, thrombocytopenic purpura.
• Gastrointestinal.  Nausea, vomiting, anorexia, epigastric distress, diarrhea, strange taste,
• Endocrine
• Others

Abrupt withdrawal of tricyclic antidepressants can cause withdrawal symptoms and the drug should be slowly discontinued over a period of time.  However, this is usually for relatively high doses of the drug, i.e. 125 mg/day.  At the low doses (10-20 mg/day) that are used for neuropathic pain, ramping down may not be necessary.

Summary and Conclusions

Tricyclic antidepressant (TCA) drugs are commonly used for depression and neuropathic pain.  In depression, they do have significant but modest effects on depression, in part because of strong placebo effects.  In neuropathic pain, however, tricyclic antidepressants have been found to be as good or better than other therapies, including anti-epileptic drugs like gabapentin and pregabalin.  However, only about a third of patients responded to TCA drugs and it provides only moderate pain relief.  On the other hand, TCA drugs are often used in combination with other drugs.  In general, TCA has more side-effects than selective serotonin re-uptake inhibitors (SSRI) and the drugs are deadly when taken in overdose.  The TCA dose of neuropathic pain is much lower than for depression and therefore should cause less side-effects and may not require systematic staged withdrawal.  On the other hand, TCA drugs interact with many drugs even at low doses and therefore treatment programs with TCA must be carefully designed and regularly reviewed.    

References

1. Moncrieff J, Wessely S and Hardy R (2004).  Active placebos versus antidepressants for depression.  Cochrane Database Syst Rev.  CD003012.  Psychiatry, University College London, Warley hospital, Mascalls Lane, Brentwood, Essex, UK, CM14 4TU. BACKGROUND: Although there is a consensus that antidepressants are effective in depression, placebo effects are also thought to be substantial. Side effects of antidepressants may reveal the identity of medication to participants or investigators and thus may bias the results of conventional trials using inert placebos. Using an ‘active’ placebo which mimics some of the side effects of antidepressants may help to counteract this potential bias. OBJECTIVES: To investigate the efficacy of antidepressants when compared with ‘active’ placebos. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis review groups’s search strategy was used to search MEDLINE (1966-2000), PsychLIT (1980-2000) and EMBASE (1974-2000) and this was last done in July 2000. Reference lists from relevant articles and textbooks were searched and 12 specialist journals were handsearched up to 1996. SELECTION CRITERIA: Randomised and quasi randomised controlled trials comparing antidepressants with active placebos in people with depression. DATA COLLECTION AND ANALYSIS: Since many different outcome measures were used a standard measure of effect was calculated for each trial. A subgroup analysis of inpatient and outpatient trials was conducted. Two reviewers independently assessed whether each trial met inclusion criteria. MAIN RESULTS: Nine studies involving 751 participants were included. Two of them produced effect sizes which showed a consistent and statistically significant difference in favour of the active drug. Combining all studies produced a pooled estimate of effect of 0.39 standard deviations (confidence interval, 0.24 to 0.54) in favour of the antidepressant measured by improvement in mood. There was high heterogeneity due to one strongly positive trial. Sensitivity analysis omitting this trial reduced the pooled effect to 0.17 (0.00 to 0.34). The pooled effect for inpatient and outpatient trials was highly sensitive to decisions about which combination of data was included but inpatient trials produced the lowest effects. REVIEWER’S CONCLUSIONS: The more conservative estimates from the present analysis found that differences between antidepressants and active placebos were small. This suggests that unblinding effects may inflate the efficacy of antidepressants in trials using inert placebos. Further research into unblinding is warranted.
2. Bramness JG, Walby FA and Tverdal A (2007).  The sales of antidepressants and suicide rates in Norway and its counties 1980-2004.  J Affect Disord.  102: 1-9.  Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway. BACKGROUND: Suicide is a major public health problem and depression is among the most important risk factors for suicide. Treatment of depression might prevent suicide. To study this hypothesis further we conducted an ecological study. METHODS: An ecological study using sales data for antidepressants and numbers of suicides in Norway and Norwegian counties 1980-2004 was performed. Data on alcohol consumption and unemployment rates were registered and taken into account. Data were analyzed using Cochrane-Orcutt time series for the country as a whole. The county specific data were analyzed with a random coefficient model with county as subject and intercept and time (slope) as random variables using an unstructured covariance matrix. RESULTS: Sales of non-tricyclic antidepressants (non-TCAs) and suicide were clearly negatively related, even when controlling for alcohol and unemployment (adjusted r(2): 0.57). There was an effect modification between time and level of sales of non-TCAs. Studying the relationship between the sales of non-TCAs and the suicide rate, we found that it was significant and stronger for the low sales figures, but non-existent for the high sales figures. LIMITATIONS: Ecological studies cannot infer causality. CONCLUSIONS: The fall in suicide rates in Norway and its counties was related to the increased sales of non-TCAs. The effect was mostly a result of a sales increase in the lower sales segment, indicating that a change from the more toxic TCAs, or heightened awareness of depression and its treatment, could explain the relationship found between sales of newer antidepressants and a decrease in suicide rate.
3. Mottram P, Wilson K and Strobl J (2006).  Antidepressants for depressed elderly.  Cochrane Database Syst Rev.  CD003491.  University of Liverpool, Department of Psychiatry, Academic Unit, St Catherine’s Hospital, Church Road, Birkenhead, UK, CH42 0LQ. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it BACKGROUND: Depression is a relatively common experience in older adults. The syndrome is associated with considerable distress, morbidity and service commitment. Approximately two thirds of patients presenting with severe forms will respond to antidepressant treatment and the last twenty years has witnessed a great increase in the number of these drugs. Older, frail people are particularly vulnerable to side effects. OBJECTIVES: The aims of this review were to examine the efficacy of antidepressant classes, to compare the withdrawal rates associated with each class and describe the side effect profile of antidepressant drugs for treating depression in patients described as elderly, geriatric, senile or older adults, aged 55 or over. SEARCH STRATEGY: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies) was searched (2003-08-13). Reference lists of relevant papers and previous systematic reviews were hand searched for published reports and citations of unpublished studies. SELECTION CRITERIA: Only randomised controlled trials were included. Trials had to compare at least two active antidepressant drugs in the treatment of depression. DATA COLLECTION AND ANALYSIS: Reviewers extracted data independently. In examining efficacy, the reviewers assumed that people who died or dropped out had no improvement. Withdrawal rates irrespective of cause and specifically due to side effects were compared between drug classes. Relative risk (RR) for dichotomous data and weighted mean difference for continuous data were calculated with 95% confidence intervals (CI). Qualitative side effect data were reported in terms of ratios of side effects and percentage of patients experiencing specific side effects. MAIN RESULTS: A total of 29 trials provided data for inclusion in the review. We were unable to find any differences in efficacy when comparing classes of antidepressants. However, as the trials contained relatively small numbers of patients, these findings may be explained by a type two error. Tricyclic antidepressants (TCAs) compared less favourably with selective serotonin reuptake inhibitors (SSRIs) in terms of numbers of patients withdrawn irrespective of reason (RR: 1.24, CI 1.04, 1.47) and number withdrawn due to side effects (RR: 1.30, CI 1.02, 1.64). Subgroup analyses demonstrated that TCA related antidepressants had similar withdrawal rates to SSRIs irrespective of reason of withdrawal (RR: 1.49, CI 0.74, 2.98) or withdrawal due to side effects (RR: 1.07, CI 0.43, 2.70). The qualitative analysis of side effects showed a small increased profile of gastro-intestinal and neuropsychiatric side effects associated with classical TCAs. AUTHORS’ CONCLUSIONS: Our findings suggest that SSRIs and TCAs are of the same efficacy. However, we have found some evidence suggesting that TCA related antidepressants and classical TCAs may have different side effect profiles and are associated with differing withdrawal rates when compared with SSRIs. The review suggests that classical TCAs are associated with a higher withdrawal rate due to side effect experience, although these results must be interpreted with caution due to the relatively small size of the review and the heterogeneity of the drugs and patient populations.
4. Nieuwenhuijsen K, Bultmann U, Neumeyer-Gromen A, Verhoeven AC, Verbeek JH and van der Feltz-Cornelis CM (2008).  Interventions to improve occupational health in depressed people.  Cochrane Database Syst Rev.  CD006237.  Academic Medical Centre, Univeriteit van Amsterdam, Coronel Institute of Occupational Health, PO Box 22700, Amsterdam, Netherlands, 1100 DE. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it BACKGROUND: Work disability such as sickness absence is common in people with depression. OBJECTIVES: To evaluate the effectiveness of interventions aimed at reducing work disability in depressed workers. SEARCH STRATEGY: We searched the CCDANCTR-Studies and CCDANCTR-References on 2/8/2006, Cochrane Library CENTRAL register, MEDLINE, EMBASE, CINAHL, PsycINFO, OSH-ROM (Occupational Safety and Health), NHS-EED, and DARE. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster RCTs of work-directed and worker-directed interventions for depressed people, using sickness absence as the primary outcome DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. We used standardised mean differences (SMD) with 95% confidence intervals (CIs) to pool study results where possible. MAIN RESULTS: We included eleven studies, all of worker-directed interventions, involving 2556 participants. Only one study addressed work issues using adjuvant occupational therapy. Other interventions evaluated anti-depressant medication (selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamino-oxidase inhibitors), psychodynamic therapy, enhanced primary care and psychological treatment. For medication, the combined results of three studies (n=864) showed no difference between antidepressant medication and alternative medication in their effect on days of sickness absence (SMD 0.09; 95% CI -0.05 to 0.23) In two pooled studies (n=969), the effect of enhanced primary care on days of sickness absence did not differ from usual care in the medium term (SMD -0.02; 95% CI -0.15 to 0.12). All other comparisons were based on single studies (n=6), all of which showed a lack of significant difference for sickness absence between groups, with the exception of one small study, combined psychodynamic therapy and TCAs versus TCAs alone, which favoured the combined treatment. AUTHORS’ CONCLUSIONS: Based on a heterogeneous sample of studies, there is currently no evidence of an effect of medication alone, enhanced primary care, psychological interventions or the combination of those with medication on sickness absence of depressed workers. In future RCTs, interventions should specifically address work issues, and occupational outcomes should be used to measure the effect.
5. Saarto T and Wiffen PJ (2007).  Antidepressants for neuropathic pain.  Cochrane Database Syst Rev.  CD005454.  Helsinki University Central Hospital, Cancer Center, Haartmaninkatu 4, P O Box 180, Helsinki, Finland, FIN-00029. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2005 of The Cochrane Library. For many years antidepressant drugs have been used to manage neuropathic pain, and are often the first choice treatment. It is not clear, however, which antidepressant is more effective, what role the newer antidepressants can play in treating neuropathic pain, and what adverse effects are experienced by patients. OBJECTIVES: To determine the analgesic effectiveness and safety of antidepressant drugs in neuropathic pain. SEARCH STRATEGY: Randomised controlled trials (RCTs) of antidepressants in neuropathic pain were identified in MEDLINE (1966 to Oct 2005); EMBASE (1980 to Oct 2005); the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, Issue 3, 2005; and the Cochrane Pain, Palliative and Supportive Care Trials Register (May 2002). Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. SELECTION CRITERIA: RCTs reporting the analgesic effects of antidepressant drugs in adult patients, with subjective assessment of pain of neuropathic origin. Studies that included patients with chronic headache and migraine were excluded. DATA COLLECTION AND ANALYSIS: Two review authors agreed the included studies, extracted data, and assessed methodological quality independently. Sixty one trials of 20 antidepressants were considered eligible (3293 participants) for inclusion. Relative Risk (RR) and Number-Needed-to-Treat (NNTs) were calculated from dichotomous data for effectiveness and adverse effects.This update includes 11 additional studies (778 participants). MAIN RESULTS: Sixty one RCTs were included in total. Tricyclic antidepressants (TCAs) are effective and have an NNT of 3.6 (95% CI 3 to 4.5) RR 2.1 (95% CI 1.8 to 2.5) for the achievement of at least moderate pain relief. There is limited evidence for the effectiveness of the newer SSRIs but no studies of SNRIs were found. Venlafaxine (three studies) has an NNT of 3.1 (95% CI 2.2 to 5.1) RR 2.2 (95% CI 1.5 to 3.1). There were insufficient data to assess effectiveness for other antidepressants such as St Johns Wort and L-tryptophan. For diabetic neuropathy the NNT for effectiveness was 1.3 (95% CI 1.2 to 1.5) RR 12.4 (95% CI 5.2 to 29.2) (five studies); for postherpetic neuralgia 2.7 (95% CI 2 to 4.1), RR 2.2 (95% CI 1.6 to 3.1) (four studies). There was evidence that TCAs are not effective in HIV-related neuropathies. The number needed to harm (NNH) for major adverse effects defined as an event leading to withdrawal from a study was 28 (95% CI 17.6 to 68.9) for amitriptyline and 16.2 (95% CI 8 to 436) for venlafaxine. The NNH for minor adverse effects was 6 (95% CI 4.2 to 10.7) for amitriptyline and 9.6 (95% CI 3.5 to 13) for venlafaxine. AUTHORS’ CONCLUSIONS: This update has provided additional confirmation on the effectiveness of antidepressants for neuropathic pain and has provided new information on another antidepressant - venlafaxine. There is still limited evidence for the role of SSRIs. Whether antidepressants prevent the development of neuropathic pain (pre-emptive use) is still unclear. Both TCAs and venlafaxine have NNTs of approximately three. This means that for approximately every three patients with neuropathic pain who are treated with either of these antidepressants, one will get at least moderate pain relief. There is evidence to suggest that other antidepressants may be effective but numbers of participants are insufficient to calculate robust NNTs. SSRIs are generally better tolerated by patients and more high quality studies are required.
6. Attal N, Cruccu G, Haanpaa M, Hansson P, Jensen TS, Nurmikko T, Sampaio C, Sindrup S and Wiffen P (2006).  EFNS guidelines on pharmacological treatment of neuropathic pain.  Eur J Neurol.  13: 1153-69.  Centre d’Evaluation at de Traitement de la Douleur, Hospital Ambroise Pare, Boulogne-Billancourt, France. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it Neuropathic pain treatment remains unsatisfactory despite a substantial increase in the number of trials. This EFNS Task Force aimed at evaluating the existing evidence about the pharmacological treatment of neuropathic pain. Studies were identified using first the Cochrane Database then Medline. Trials were classified according to the aetiological condition. All class I and II controlled trials (according to EFNS classification of evidence) were assessed, but lower-class studies were considered in conditions that had no top level studies. Only treatments feasible in an outpatient setting were evaluated. Effects on pain symptoms/signs, quality of life and comorbidities were particularly searched for. Most of the randomized controlled trials included patients with postherpetic neuralgia (PHN) and painful polyneuropathies (PPN) mainly caused by diabetes. These trials provide level A evidence for the efficacy of tricyclic antidepressants, gabapentin, pregabalin and opioids, with a large number of class I trials, followed by topical lidocaine (in PHN) and the newer antidepressants venlafaxine and duloxetine (in PPN). A small number of controlled trials were performed in central pain, trigeminal neuralgia, other peripheral neuropathic pain states and multiple-aetiology neuropathic pains. The main peripheral pain conditions respond similarly well to tricyclic antidepressants, gabapentin, and pregabalin, but some conditions, such as HIV-associated polyneuropathy, are more refractory. There are too few studies on central pain, combination therapy, and head-to-head comparison. For future trials, we recommend to assess quality of life and pain symptoms or signs with standardized tools.
7. Namaka M, Gramlich CR, Ruhlen D, Melanson M, Sutton I and Major J (2004).  A treatment algorithm for neuropathic pain.  Clin Ther.  26: 951-79.  University of Manitoba, Health Sciences Centre, Winnipeg, Manitoba R3T 2N2, Canada. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it BACKGROUND: Neuropathic pain is a chronic pain syndrome caused by drug-, disease-, or injury-induced damage or destruction of sensory neurons within the dorsal root ganglia of the peripheral nervous system. Characteristic clinical symptoms include the feeling of pins and needles; burning, shooting, and/or stabbing pain with or without throbbing; and numbness. Neuronal hyperexcitability represents the hallmark cellular mechanism involved in the underlying pathophysiology of neuropathic pain. Although the primary goal is to alleviate pain, clinicians recognize that even the most appropriate treatment strategy may be, at best, only able to reduce pain to a more tolerable level. OBJECTIVE: The purpose of this review is to propose a treatment algorithm for neuropathic pain that health care professionals can logically follow and adapt to the specific needs of each patient. The algorithm is intended to serve as a general guide to assist clinicians in optimizing available therapeutic options. METHODS: A comprehensive review of the literature using the PubMed, MEDLINE, Cochrane, and Toxnet databases was conducted to design and develop a novel treatment algorithm for neuropathic pain that encompasses agents from several drug classes, including antidepressants, antiepileptic drugs, topical antineuralgic agents, narcotics, and analgesics, as well as various treatment options for refractory cases. RESULTS: Any of the agents in the first-line drug classes (tricyclic antidepressants, antiepileptic drugs, topical antineuralgics, analgesics) may be used as a starting point in the treatment of neuropathic pain. If a patient does not respond to treatment with at least 3 different agents within a drug class, agents from a second drug class may be tried. When all first-line options have been exhausted, narcotic analgesics or refractory treatment options may provide some benefit. Patients who do not respond to monotherapy with any of the first- or second-line agents may respond to combination therapy or may be candidates for referral to a pain clinic. Because the techniques used at pain clinics tend to be invasive, referrals to these clinics should be reserved for patients who are truly refractory to all forms of pharmacotherapy. CONCLUSIONS: Neuropathic pain continues to be one of the most difficult pain conditions to treat. With the proposed algorithm, clinicians will have a framework from which to design a pain treatment protocol appropriate for each patient. The algorithm will also help streamline referrals to specialized pain clinics, thereby reducing waiting list times for patients who are truly refractory to traditional pharmacotherapy.
8. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV and Loubser PG (2007).  Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury.  Arch Phys Med Rehabil.  88: 1547-60.  Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA. This e-mail address is being protected from spam bots, you need JavaScript enabled to view it OBJECTIVE: To test the hypotheses that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than an active placebo, diphenhydramine. DESIGN: Randomized, controlled, double blind, triple crossover 8-week trial. SETTING: Veterans Affairs medical center. PARTICIPANTS: Community dwelling adults with spinal cord injury (N=38) were recruited by telephone, letters, and flyers. INTERVENTION: Eight-week trial each of amitriptyline, gabapentin, and diphenhydramine. MAIN OUTCOME MEASURES: Pain intensity measured with a 10-cm visual analog scale (VAS) and an 11-point (0-10) numeric rating scale (NRS) and depressive symptomatology measured with the Center for Epidemiologic Studies Depression Scale-Short Form (CESD-SF). RESULTS: Baseline VAS scores for participants with low (< 10) CESD-SF scores was 4.61 and for those with high scores (> or = 10) it was 7.41. At week 8, in participants with high baseline CESD-SF scores, amitriptyline (mean, 4.21) was more effective than diphenhydramine (mean, 6.67; P=.035), and there was a nonsignificant trend suggesting that amitriptyline may be more effective than gabapentin (mean, 6.68; P=.061). Gabapentin was no more effective than diphenhydramine (P=.97). There was no significant difference among the medications for those with lower CESD-SF scores. Results could not be attributed to dropout rates, order or dose of medications, amount of medication taken for breakthrough pain, or side effects. CONCLUSIONS: Amitriptyline is more efficacious in relieving neuropathic pain than diphenhydramine at or below the level of spinal cord injury in people who have considerable depressive symptomatology.