Ronald Dubner

Effects of Desipramine, Amitriptyline, and Fluoxetine on Pain in Diabetic Neuropathy

BACKGROUND Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drugs many pharmacologic actions. Selective agents might be safer and more effective. METHODS We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period. RESULTS After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients. CONCLUSIONS Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.

The neural basis of oral and facial function

This article provides an outline of the neural mechanisms that are involved in the somatosensory and motor functions of the face and mouth and, in a more limited sense, of the pharynx and larynx. The article focuses on the neural basis of orofacial touch, temperature, and pain and gives particular emphasis to the latter, because pain commonly occurs in the skin, teeth, muscles, joint, and other tissues of the orofacial region and humans can have long-term suffering from several pain states or syndromes in the face and mouth. Particular attention is also given to the neural processes underlying the many reflex and other motor functions manifested in the orofacial region, especially those related to mastication (chewing), swallowing, and associated neuromuscular functions. Few details are provided of some other important functions of the face and mouth (e.g., smell, taste, speech).

Interactions between the immune and nervous systems in pain

Immune cells and glia interact with neurons to alter pain sensitivity and to mediate the transition from acute to chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury. Immune cells not only contribute to immune protection but also initiate the sensitization of peripheral nociceptors. Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glia and neurons form an integrated network that coordinates immune responses and modulates the excitability of pain pathways. The immune system also reduces sensitization by producing immune-derived analgesic and anti-inflammatory or proresolution agents. A greater understanding of the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and new therapeutic opportunities for managing chronic pain.

Towards a mechanism-based classification of pain?

It is self evident that the recent explosive growth in our understanding of the molecular, cellular and system’s mechanisms responsible for nociception and pain has important implications for the clinical diagnosis and treatment of pain. A small group of independent basic scientists and clinicians met in New York in January 1998, for a wide ranging discussion on the possible need for and implications of a mechanism-based classification of pain. The group believed that acceptance of a mechanism-based classification could have profound implications: drugs may be developed which target distinct mechanisms, basic scientists may have new guidelines for experimental design, and clinicians may be eventually armed with more reliable and valid diagnostic tools for treatment and clinical investigation. Furthermore, a mechanism-based classification for clinical syndromes might generate testable hypotheses for selecting treatments which interact with specific mechanisms. We wish to initiate a wide debate on this important topic by highlighting what we consider to be some of the key issues. In general, taxonomies can be either natural or artificial. Examples of each, respectively, are the division of objects into animate or inanimate groups (which reflects order in nature) and a telephone book (which is merely a conventional way of listing peoples’ numbers and addresses). Natural taxonomies are based on theoretical ideas of how the world is organized. Artificial taxonomies provide convenient or practical methods for organizing the world. Consequently they do not easily facilitate the development of new ideas. A mechanism-based classification of pain requires a conceptual understanding of organization in nature, and would, therefore, set a framework for scientific development. Current methods of classifying pain have, we believe, a number of major limitations. Pain syndromes are identified by parts of the body, duration, and causative agent. We believe that an anatomical-based classification of pain is limiting because the innervation of distinct anatomical regions is often analogous, bearing in mind differences of target organ innervated (e.g. skin vs. viscera), length of axon, myelination, etc. To the extent that universal mechanisms can be identified, anatomical differences should be disregarded in favor of mechanisms that apply to all parts of the body. The acute/chronic dichotomy is also not helpful. Acute and chronic do not readily differentiate mechanisms. The benign/malignant dichotomy too has no mechanistic basis for pain, although it will influence treatment strategies. Greater care needs also to be taken with the definition of terms such as allodynia and hyperalgesia. Both terms are a description of clinical symptoms and do not imply a mechanism. Allodynia (pain evoked by normally non-painful stimuli) is often used in the clinical context to refer to Ab-fiber mediated brush-evoked mechanical pain or an altered processing of sensory information in the CNS. However, there are several other distinct types of mechanical hypersensitivity that do not involve A b fibers and probably no significant central reorganization, but which present as pain evoked by commonly non-painful stimuli. Reduction in threshold is not, therefore, useful by itself, for a mechanistic classification. From a practical perspective, clinicians use classification systems to predict treatment responses as well as prognosis and to search for risk factors and morbidities. Ultimately any classification system must be judged on its utility for clinical practice and research. The most powerful systems could be organized by mechanism, by disease or etiology. In the neuropathic disease category, at least, the disease classification system was considered by the group to fail to Pain 77 (1998) 227–229

Descending modulation in persistent pain: an update

Our knowledge of the existence of endogenous descending pain modulatory systems spans at least three decades and we now know that brain stem descending pathways constitute a major mechanism in the control of pain transmission (for comprehensive reviews, see Fields and Basbaum, 1999; Millan, 2002). The basis for an endogenous descending pain modulatory circuit linking the periaqueductal gray (PAG), the rostral ventromedial medulla (RVM) and the spinal cord, has now been well established (Gebhart, 1986; Fields et al., 1991; Fields and Basbaum, 1999; Millan, 2002 for reviews). Recent studies indicate that hyperalgesia in animal models of inflammatory and neuropathic pain is closely linked to activation of descending modulatory circuits involving both inhibition and facilitation. This review will discuss recent conceptual advances in our understanding of descending modulation and its role in persistent pain. The following issues will be described below: (1) the existence of bidirectional descending control; (2) descending modulatory influences after tissue and nerve injury; (3) dynamic shifts in descending modulation after injury; and (4) molecular mechanisms of activity-dependent plasticity in descending modulatory circuitry. The clinical implications of the findings will then be discussed.

Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain.

The emerging literature implicates a role for glia/cytokines in persistent pain. However, the mechanisms by which these non-neural elements contribute to CNS activity-dependent plasticity and pain are unclear. Using a trigeminal model of inflammatory hyperalgesia, here we provide evidence that demonstrates a mechanism by which glia interact with neurons, leading to activity-dependent plasticity and hyperalgesia. In response to masseter inflammation, there was an upregulation of glial fibrillary acidic proteins (GFAPs), a marker of astroglia, and interleukin-1β (IL-1β), a prototype proinflammatory cytokine, in the region of the trigeminal nucleus specifically related to the processing of deep orofacial input. The activated astroglia exhibited hypertrophy and an increased level of connexin 43, an astroglial gap junction protein. The upregulated IL-1β was selectively localized to astrocytes but not to microglia and neurons. Local anesthesia of the masseter nerve prevented the increase in GFAP and IL-1β after inflammation, and substance P, a prototype neurotransmitter of primary afferents, induced similar increases in GFAP and IL-1β, which was blocked by a nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. Injection of IL-1 receptor antagonist and fluorocitrate, a glial inhibitor, attenuated hyperalgesia and NMDA receptor phosphorylation after inflammation. In vitro application of IL-1β induced NR1 phosphorylation, which was blocked by an IL-1 receptor antagonist, a PKC inhibitor (chelerythrine), an IP3 receptor inhibitor (2-aminoethoxydiphenylborate), and inhibitors of phospholipase C [1-[6-((17b-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-2,5-dione] and phospholipase A2 (arachidonyltrifluoromethyl ketone). These findings provide evidence of astroglial activation by tissue injury, concomitant IL-1β induction, and the coupling of NMDA receptor phosphorylation through IL-1 receptor signaling.

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

&NA; 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.

Supraspinal Glial-Neuronal Interactions Contribute to Descending Pain Facilitation

Spinal glial reaction and proinflammatory cytokine induction play an important role in the development of chronic pain states after tissue and nerve injury. The present study investigated the cellular and molecular mechanisms underlying descending facilitation of neuropathic pain with an emphasis on supraspinal glial–neuronal relationships. An early and transient reaction of microglia and prolonged reaction of astrocytes were found after chronic constriction injury (CCI) of the rat infraorbital nerve in the rostral ventromedial medulla (RVM), a major component of brainstem descending pain modulatory circuitry. There were prolonged elevations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) after CCI, and they were expressed in RVM astrocytes at 14 d after injury. Intra-RVM injection of microglial and astrocytic inhibitors attenuated mechanical hyperalgesia and allodynia at 3 and 14 d after CCI, respectively. Moreover, TNFR1 and IL-1R, receptors for TNF-α and IL-1β, respectively, were expressed primarily in RVM neurons exhibiting immunoreactivity to the NMDA receptor (NMDAR) subunit NR1. CCI increased TNFR1 and IL-1R levels and NR1 phosphorylation in the RVM. Neutralization of endogenous TNF-α and IL-1β in the RVM significantly reduced CCI-induced behavioral hypersensitivity and attenuated NR1 phosphorylation. Finally, intra-RVM administration of recombinant TNF-α or IL-1β upregulated NR1 phosphorylation and caused a reversible and NMDAR-dependent allodynia in normal rats, further suggesting that TNF-α and IL-1β couple glial hyperactivation with NMDAR function. These studies have addressed a novel contribution of supraspinal astrocytes and associated cytokines as well as central glial–neuronal interactions to the enhancement of descending facilitation of neuropathic pain.

Neuron-glia crosstalk gets serious: Role in pain hypersensitivity

PURPOSE OF REVIEW Recent studies show that peripheral injury activates both neuronal and nonneuronal or glial components of the peripheral and central cellular circuitry. The subsequent neuron-glia interactions contribute to pain hypersensitivity. This review will briefly discuss novel findings that have shed light on the cellular mechanisms of neuron-glia interactions in persistent pain. RECENT FINDINGS Two fundamental questions related to neuron-glia interactions in pain mechanisms have been addressed: what are the signals that lead to central glial activation after injury and how do glial cells affect central nervous system neuronal activity and promote hyperalgesia? SUMMARY Evidence indicates that central glial activation depends on nerve inputs from the site of injury and release of chemical mediators. Hematogenous immune cells may migrate to/infiltrate the brain and circulating inflammatory mediators may penetrate the blood-brain barrier to participate in central glial responses to injury. Inflammatory cytokines such as interleukin-1beta released from glia may facilitate pain transmission through its coupling to neuronal glutamate receptors. This bidirectional neuron-glia signaling plays a key role in glial activation, cytokine production and the initiation and maintenance of hyperalgesia. Recognition of the contribution of the mutual neuron-glia interactions to central sensitization and hyperalgesia prompts new treatment for chronic pain.

Nucleus reticularis gigantocellularis and nucleus raphe magnus in the brain stem exert opposite effects on behavioral hyperalgesia and spinal Fos protein expression after peripheral inflammation

Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freunds adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending pathways. The imbalance of these modulating systems may be one mechanism underlying variability in acute and chronic pain conditions.