GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence.

We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.

Pain perception is altered by a nucleotide polymorphism in SCN9A.

The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype.

Expansion of the human mu-opioid receptor gene architecture: novel functional variants.

The mu-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5'-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.

Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1.

Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury.

Does the pain-protective GTP cyclohydrolase haplotype significantly alter the pattern or severity of pain in humans with chronic pancreatitis?

BACKGROUND: Pain is often a dominant clinical feature of chronic pancreatitis but the frequency and severity is highly variable between subjects. We hypothesized that genetic polymorphisms contribute to variations in clinical pain patterns. Since genetic variations in the GTP cyclohydrolase (GCH1) gene have been reported to protect some patients from pain, we investigated the effect of the "pain protective haplotype" in well characterized patients with chronic pancreatitis (CP) or recurrent acute pancreatitis (RAP) from the North American Pancreatitis Study 2 (NAPS2). RESULTS: Subjects in the NAPS2 study were asked to rank their pain in one of 5 categories reflecting different levels of pain frequency and severity. All subjects were genotyped at rs8007267 and rs3783641 to determine the frequency of the GCH1 pain-protective haplotype. In Caucasian subjects the frequency of the pain-protective GCH1 haplotype was no different in the control group (n = 236), CP patients (n = 265), RAP patients (N = 131), or in CP patients subclassified by pain category compared to previously reported haplotype frequencies in the general Caucasian population. CONCLUSION: The GCH1 pain-protective haplotype does not have a significant effect on pain patterns or severity in RAP or CP. These results are important for helping to define the regulators of visceral pain, and to distinguish different mechanisms of pain.

Morphine versus mexiletine for treatment of postamputation pain: a randomized, placebo-controlled, crossover trial.

BACKGROUND: Stump and phantom pains are debilitating sequelae of amputations that are often resistant to treatment. The efficacy of pharmacologic therapies, including opioids and sodium channel blockers, for postamputation pain is uncertain. METHODS: The authors conducted a double-blind, randomized, placebo-controlled, crossover study in adult patients with postamputation pain of 6 months or longer and greater than 3 on a 0-10 numeric pain rating scale. Each of the three treatment periods (morphine, mexiletine, or placebo) included a 1-week drug-free interval followed by 4-week titration, 2-week maintenance, and 2-week drug-taper phases. The primary outcome measure was change in average pain intensity from the drug-free baseline to the last week of maintenance. RESULTS: Sixty amputees were enrolled; data were analyzed from 56 subjects for one drug period, 45 subjects for two drug periods, and 35 subjects who completed all three drug periods. The mean morphine and mexiletine dosages were 112 and 933 mg, respectively. Morphine treatment provided lower pain scores compared with placebo and mexiletine (P = 0.0003). The mean percent pain relief during treatment with placebo, mexiletine, and morphine was 19, 30, and 53%, respectively (P < 0.0001, morphine vs. placebo and mexiletine). The numbers needed to treat to obtain 50% and 33% decreases in pain intensity with morphine were 5.6 and 4.5, respectively. Treatment with morphine was associated with a higher rate of side effects. CONCLUSIONS: Therapy with morphine, but not mexiletine, resulted in a decrease in intensity of postamputation pain but was associated with a higher rate of side effects and no improvement in self-reported levels of overall functional activity and pain-related interference in daily activities.

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

BACKGROUND: Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. RESULTS: We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor alpha1 subunit, GABA-A receptor alpha2 subunit, GABA-A receptor beta1 subunit, alpha-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor beta1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks. CONCLUSION: If confirmed, the current results may suggest that a common haplotype in the GABA-A beta1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.

Low intensity permanent magnets in the treatment of chronic lumbar radicular pain.

We assessed the pain-relieving efficacy of static magnetic fields produced by 200 Gauss (G) magnets compared with 50G magnets in a double-blind, randomized, two-phase crossover study in patients with chronic lumbar radicular pain. The surface field strengths of the magnets were 200 and 50G. Phase I included four random periods of two-week duration: two periods with 200G, one period with 50G, and one period of "no treatment." The magnets were positioned either vertically or horizontally in standard lumbosacral elastic corsets. Phase II consisted of two five-week periods with the most effective magnet from Phase I and its corresponding 50 or 200G device. The primary outcome was average daily leg pain score (0-10 scale) in each period of Phase II. Thirty-eight of 40 randomized patients completed Phase I, and 28 of 31 Phase II participants completed the study. In Phase I, pain scores did not differ significantly between 200 and 50G magnets. Phase II average leg pain scores tended to be lower with 200 vs. 50G magnets (3.2+/-2.1 for 200G vs. 3.9+/-2.2 for 50G magnets [P=0.08]) after excluding one unblinded patient. The relative treatment effect of the 200G magnets appeared to increase throughout the five-week period. Although these data cannot rule out a chance effect, the positive trends suggest that larger, longer-duration, sham-controlled trials with 200G magnets be considered in patients with chronic lumbar radicular pain.

Effects of chronic osteoarthritis pain on neuroendocrine function in men.

CONTEXT: Chronic pain has been associated with elevated cortisol, reduced LH and testosterone (T), and/or augmented circulating or excreted catecholamines. Most endocrine studies have been conducted in patients in whom the potentially confounding effects of depression, inflammatory disease, or coexistent medication use have not been controlled. OBJECTIVE: The objective of the study was to test the hypothesis that chronic pain activates ACTH-cortisol and suppresses LH-T. DESIGN AND SETTING: This was a case control study conducted at a clinical research center. PARTICIPANTS: Participants included 16 opioid-naive men with chronic osteoarthritis pain, aged 35-65 yr with body mass index 20-30 kg/m2, and 12 healthy, opioid- and pain-free men of similar ages and body mass indexes. METHODS: We compared circulating concentrations of ACTH, cortisol, LH, and T derived from every 20-min blood sampling (2000-0800 h), and 24-h urinary excretion of cortisol, epinephrine, norepinephrine, and dopamine. RESULTS: There were no significant differences in mean or integrated concentrations of ACTH, cortisol, LH, or T, or in the corresponding approximate entropy scores in osteoarthritis patients, compared with control subjects. The 0800-h serum LH concentrations were elevated in patients vs. controls (6.42 +/- 1.65 vs. 3.99 +/- 1.54 IU/liter, mean +/- sd, P = 0.02), whereas there were no significant group differences in total or free T, SHBG, cortisol binding globulin, dehydroepiandrosterone sulfate, or urinary cortisol and catecholamines. CONCLUSIONS: These data suggest that neuroendocrine function is not significantly altered in otherwise healthy men with chronic musculoskeletal pain and that prior reports of such hormonal abnormalities may have resulted from the confounding effects of coexistent illness or medication use.

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety.

BACKGROUND: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. RESULTS: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood--the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. CONCLUSION: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.

Use of the cumulative proportion of responders analysis graph to present pain data over a range of cut-off points: making clinical trial data more understandable.

In randomized controlled trials, no single definition of response is ideal for all purposes. We propose a method to present in a simple fashion the likelihood of response over a full range of response levels, which will facilitate a better understanding of clinical trial data. We present the technique called the cumulative proportion of responders analysis (CPRA) and its application to four pain clinical trial data sets as examples. The CPRA can be used to present the proportion of responders over the entire range of possible cut-off points as a graph. This allows the reader to compare treatment groups at any responder level that is valid for their patient population. Whether as a primary or secondary approach to a clinical trial of pain therapy, the display of data in a CPRA format may be useful in the understanding of results and applicability to patient care.

Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans.

The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.

Topiramate in chronic lumbar radicular pain.

UNLABELLED: Chronic lumbar radicular pain is the most common neuropathic pain syndrome. This was a double-blind, randomized, 2-period crossover trial of topiramate (50 to 400 mg) and diphenhydramine (6.25 to 50 mg) as active placebo to assess the efficacy of topiramate. Each period consisted of a 4-week escalation, a 2-week maintenance at the highest tolerated dose, and a 2-week taper. Main outcome was the mean daily leg pain score on a 0 to 10 scale during the maintenance period. Global pain relief was assessed on a 6-level category scale. In the 29 of 42 patients who completed the study, topiramate reduced leg pain by a mean of 19% (P = .065). Global pain relief scores were significantly better on topiramate (P < .005). Mean doses were topiramate 200 mg and diphenhydramine 40 mg. We concluded that topiramate treatment might reduce chronic sciatica in some patients but causes frequent side effects and dropouts. We would not recommend topiramate unless studies of alternative regimens showed a better therapeutic ratio. PERSPECTIVE: The anticonvulsant topiramate might reduce chronic lumbar nerve root pain through effects such as blockade of voltage-gated sodium channels and AMPA/kainite glutamate receptors, modulation of voltage-gated calcium channels, and gamma-aminobutyric acid agonist-like effects.

Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations.

Chronic neuropathic pain, caused by lesions in the peripheral or central nervous system, comes in many forms. We describe current approaches to the diagnosis and assessment of neuropathic pain and discuss the results of recent research on its pathophysiologic mechanisms. Randomized controlled clinical trials of gabapentin, the 5% lidocaine patch, opioid analgesics, tramadol hydrochloride, and tricyclic antidepressants provide an evidence-based approach to the treatment of neuropathic pain, and specific recommendations are presented for use of these medications. Continued progress in basic and clinical research on the pathophysiologic mechanisms of neuropathic pain may make it possible to predict effective treatments for individual patients by application of a pain mechanism-based approach.

Mapping a gene for neuropathic pain-related behavior following peripheral neurectomy in the mouse.

Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self-injury of the anesthetic limb ("autotomy"). Since the same denervation produces phantom limb pain and anesthesia dolorosa in humans, autotomy has been used as a model of human neuropathic pain. Autotomy is an inherited trait in rodents, attributable to a few genes of major effect. Here we used recombinant inbred (RI) mouse lines of the AXB-BXA RI set to map a gene for autotomy. Autotomy levels following unilateral sciatic and saphenous nerve section were scored daily for 36 days, using a standardized scale, in all 23 RI lines available for this set. We used a genetic map of 395 marker loci and a permutation-based statistical method for categorical data to assess the statistical significance of mapping results. We identified a marker on chromosome 15 with statistical support (P=0.0003) in the range considered significant for genome-wide scans in the mouse. Several genes located in this chromosomal region encode for neural functions related to neuropathic pain and may indicate targets for development of novel analgesics.

Single doses of the serotonin agonists buspirone and m-chlorophenylpiperazine do not relieve neuropathic pain.

A large body of evidence links serotonin with analgesia in animal models, but the lack of serotonin agonists suitable for clinical use has delayed study of serotonin's relevance to pain relief in humans. In a randomized, double-blind crossover study, we compared single doses of two 5-HT1 agonists, buspirone and m-chlorophenylpiperazine, to placebo in 20 patients with post-herpetic neuralgia or painful neuropathy. No analgesia was observed after either drug, at doses high enough to produce frequent central nervous system side effects. These results suggest that acute stimulation of 5-HT1 receptors is not sufficient to produce analgesia in patients with these neuropathic pain syndromes.

Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects.

The importance of N-methyl-D-aspartate (NMDA) receptor-mediated sensitization of central nervous system (CNS) neurons is well established in animal models of acute and chronic pain. A human model of central sensitization would be useful in screening new NMDA antagonists and establishing dose regimens for clinical trials in patients with pain related to sensitization of CNS neurons. We used this model to examine the effects of intravenous infusions of two centrally acting analgesics, the NMDA receptor antagonist ketamine and the morphine-like opioid agonist alfentanil. Twelve normal subjects completed a 3-session, randomized, double-blind, crossover study. From 25 to 60 min after capsaicin injection, subjects were given intravenous infusions of ketamine (mean dose: 32 mg), alfentanil (mean dose: 3075 micrograms), or saline placebo. Both drugs significantly reduced ongoing pain and pinprick-evoked hyperalgesia during the infusion. The reduction in allodynia evoked by light stroking was statistically significant only for alfentanil. Mean reduction +/- SEM relative to placebo were for ongoing pain: ketamine, 36 +/- 9%; alfentanil, 51 +/- 5%; area of pinprick hyperalgesia: ketamine, 34 +/- 7%; alfentanil, 35 +/- 7%; and area of mechanical allodynia: ketamine, 52 +/- 20%; alfentanil, 70 +/- 12%. Because the drugs were given systemically and produced side effects in all subjects, we cannot specify the site or sites of action nor conclusively rule out a non-specific 'active placebo' response as the cause for reduction of symptoms. Arguing against an 'active placebo' response, however, was the lack of analgesic effect of intravenous midazolam (mean dose; 3.4 mg, titrated to produce side effects of similar magnitude to ketamine and alfentanil) given at 145 min after capsaicin in 9 subjects who had received saline from 25 to 60 min. The results of this study suggest that neural systems sensitive to NMDA receptor antagonists and opioids participate in capsaicin-evoked pain phenomena, and support the feasibility of pharmacological studies using the intradermal capsaicin model.

Transdermal clonidine versus placebo in painful diabetic neuropathy.

In a randomized, double-blind, 2-period crossover study, 24 patients with pain due to diabetic polyneuropathy received transdermal clonidine, 0.3 mg/day, and placebo patches, each for 6 weeks. Pain was assessed daily by a 13-word descriptor list. Mean daily pain scores for the 6th week, the primary outcome variable, averaged 13% lower with clonidine than with placebo (95% conf. lim. for clonidine effect: 29% reduction to 3% increase in pain), which was not statistically significant (P = 0.11, 2-tailed paired t test). After this study, however, 9 patients who wished to continue clonidine had single (3 patients) or multiple (6 patients) cycles of clonidine withdrawal and rechallenge. Seven of 9 patients consistently reported return of pain with patch withdrawal followed by relief upon retreatment. One patient had an equivocal response, and the other patient had no relief upon retreatment. The 7 responders appeared similar to the other 17 patients in pain quality and neurological exam. We conclude that there may be a subset of patients with diabetic polyneuropathy who respond to transdermal clonidine. Further research is needed to identify features of neuropathic pain that predict drug response and to develop study designs that are more sensitive to a response in a subset of patients.

The analgesic efficacy of intrathecal D-Ala2-D-Leu5-enkephalin in cancer patients with chronic pain.

D-Ala-D-Leu-enkephalin (DADL) is a pentapeptide which, compared to morphine, preferentially binds to the delta receptor. We compared the analgesic and side effects of intrathecal (i.t.) DADL and i.t. morphine sulfate (MS) in 10 tolerant cancer patients with chronic pain at or below the T12 level who were receiving inadequate relief or unacceptable side effects from systemic opiates. These patients were given i.t. DADL and i.t. MS in a randomized, double-blind, cross-over study on separate days at least 1 day apart. I.t. DADL produced analgesia in all patients tested. Total pain relief was greater with DADL than MS in 6 patients, equal in 1 patient and less with DADL in 3. Side effects, most commonly drowsiness, were similar with both MS and DADL and suggest supraspinal effects by both drugs. At the doses given i.t. DADL produced effective pain relief in patients tolerant to systemic opiates although no significant difference in analgesic efficacy between MS and DADL was observed. Studies of the relative analgesic potency of i.t. DADL in man are necessary to fully assess its value in those patients tolerant to systemic or i.t. opiates.

Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial.

Although amitriptyline relieves pain in many patients with painful diabetic neuropathy, side effects often preclude effective treatment. Desipramine has the least anticholinergic and sedative effects of the first generation tricyclic antidepressants. We compared a 6 week course of desipramine (mean dose, 201 mg/day) to active placebo in 20 patients with painful diabetic neuropathy in a double-blind crossover trial. Pain relief with desipramine was statistically significant in weeks 5 and 6. Eleven patients reported at least moderate relief with desipramine, compared to 2 with placebo. Pain relief tended to be greater in depressed patients, but relief was also observed in patients who did not show an antidepressant effect. We conclude that desipramine relieves pain in many patients with painful diabetic neuropathy, offering an alternative for patients unable to tolerate amitriptyline. Blockade of norepinephrine reuptake, an action shared by desipramine, amitriptyline, and other antidepressants proven effective in neuropathic pain, may mediate this analgesic effect.