Evaluation of Neuropathic Pains - Case Study Example

The definition of neuropathic pain according to the International Association for the Study of Pain (IASP) is “all pains initiated or caused by a primary lesion or dysfunction of the nervous system” (Bouhassira, 2001). Such a definition differentiates neuropathic pains from nociceptive pains, mainly on the basis that neuropathic pain responds poorly to common analgesics (Bouhassira, 2001). The clinical features include positive and negative phenomena. Paresthesia and/or dysesthesia, which are abnormal nonpainful sensations, constitute positive phenomena. Neurological sensory deficits and other deficits (motor, cognitive, etc.) constitute negative phenomena (Bouhassira, 2001). Common conditions like traumatic nerve injury, diabetic neuropathy, AIDS neuropathy, post-herpetic neuralgia etc. are examples of painful peripheral neuropathies. Central pains are not unusual and may be seen after stroke (8%), spinal cord injury (30-50%), and multiple sclerosis (20-25%) (Bouhassira, 2001). Evaluation of neuropathic pains After assessment with standard clinical examination, assessment, and quantification of spontaneous pains, evoked pains and sensory deficits are required. To evaluate spontaneous ongoing pain visual analog scales (VAS) are used. By counting the number of paroxysms, which occur daily and measuring their intensity on a VAS, it is possible to asses paroxysmal pains. Evoked pains can be evaluated by quantitative sensory tests (QST). A cotton swab or a brush can be used to evaluate dynamic mechanical allodynia (Bouhassira, 2001). Clinically, the testing is done in the painful area and the results are compared to a nonpainful area. For the diagnosis and quantification of allodynia, pain threshold measurements are required. The assessment of hyperalgesia requires the application of suprathreshold stimuli, and the measured on a VAS, the response to each stimulus. From these inputs, stimulus-response curves can be built. An increase in the slope of the curve corresponds to hyperalgesia (Bouhassira, 2001.) Anticonvulsants Gabapentin (1-(aminomethyl)cyclohexaneacetic acid) is commonly used for neuropathic pain. More wider of this drug is, however, limited due to its side effects and frequency of dosing regimen (3-4 times daily) (Butera, 2007). The daily dose ranges from 600mg to 3600 mg (Nurmikko, 1998). Pregabalin ((S)-3- (aminomethyl)-5-methylhexanoic acid) is a newly launched drug, which is a 3-substituted analogue of ç-aminobutyric acid (GABA). One advantage of this drug over gabapentin is a more convenient dosing regimen. This is possible because of the fact that pregabalin has a bioavailability of 90%, which gives it a better pharmacokinetic profile. The exact mechanism of gabapentin and pregabalin are not clear but they may be due to their binding to the R2-ä subunit of voltage-gated Ca2+ channels. This inhibits the influx of calcium into neuronal cells, leading to neurotransmitter release inhibition, and thus, blocking neuropathic pain (Butera, 2007.) Glutamate is a neurotransmitter, which plays a role in central sensitization. Lamotrigine blocks both neuronal sodium channels as well as inhibits excessive release of glutamate. Studies have shown that lamotrigine could inhibit hyperalgesia and allodynia (Nakamura-Craig & Follenfant, 1992). In another placebo controlled study, lamotrigine, when used along with moderate doses of carbamazepine could control the pain in refractory trigeminal neuralgia (Zakrewska et al.,1997). In addition to neuropathic pain, there is evidence that lamotrigine is effective in reducing central pain, which is otherwise difficult to reduce, although this is possible only at high doses of 600mg/day (Canavera & Bonicalzi, 1996). Common adverse effects include skin complications, which could be severe; other adverse effects are similar to that of other anticonvulsants. A low initial dose of 25 to 50mg/day with gradual increase of the dose, reduces the risk of side effects (Nurmikko, 1998). Recently, the role and function of the KCNQ K+ family of channels (Kv7) in the regulation of neuronal excitability and nociception has been discussed. Since they are located in the spinal cord, dorsal root ganglion and CNS, they are an ideal target in the treatment of neuropathic pain. All KCNQ channels have the ability to couple to muscarinic receptors and form M-currents, which are inhibited by acetylcholine. The prototypical Kv7 channel opener is retigabine, which is basically an anticonvulsant. In rodent models, retigabine and its analogues have been found to attenuate neuropathic and nociceptive pain behaviors, and are able to hyperpolarize neuronal cells (Butera, 2007.) Analgesics Tramadol is a weak opiate, which acts centrally. It modulates central serotoninergic and noradrenergic inhibition of pain. The risk of addiction is low. Some of the adverse effects include: dizziness, sedation, and nausea (Nurmikko, 1998). Meloxicam has a selective inhibitory action on the enzyme cyclooxygenase 2 (less on cyclooxygenase 1). Nabumetone is a prodrug, and its active metabolite, 6-methoxy-2-naphthylacetic acid, has a preferential inhibitory action on cyclooxygenase 2. Nabumetone has been shown to be having comparable results as diclofenac used in osteoarthritis. Both nabumetone and meloxicam have been shown to have a low rate of serious gastrointestinal adverse effects (Nurmikko, 1998). Capsaicin (N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methyl-(6E)-6-nonenamide), is obtained from hot chilli peppers, and has a pungent odor (Butera, 2007). It available as a topical ointment in concentrations of 0.025% and 0.075% (Nurmikko, 1998). Studies have demonstrated that it has a strong agonist action for the transient receptor potential channel, vanilloid type 1 (TRPV1). Initially, the topical application of capsaicin cream, causes a burning sensation on the skin but later, produces analgesia (Butera, 2007). Other than the burning sensation on application, other side effects include reactions to inhaled residue of dried capsaicin, and local erythema (Nurmikko, 1998). The mechanism of action is believed to be due to the production of a constant high level of intracellular Ca2+. This causes a desensitization of the nociceptors fibers and thus, blocks neuropathic pain. Currently, capsaicin transdermal patch (NGX-4010) has been advocated in relieving HIV related neuropathic pain and postherpetic neuropathy (Butera, 2007). When compared to capsaicin cream, this patch can be used in a high-dose (8%), and is thus more beneficial (Butera, 2007.) Numerous TRPV1 antagonists are currently being developed for neuropathic pain. Capsazepine is one such prototype TRPV1 antagonist. This is related to capsaicin, and has been observed to block pain in rodent models and found to be useful in the study of TRPV1 antagonism in rodent models. Some of the other TRPV1 antagonists, which are being studied are thiourea, amide structures, and urea (Butera, 2007.) Local treatment The FDA has approved the use of lidocaine patch in the treatment of postherpetic neuralgia. The mechanism of its action is sodium channel blockade, leading to a depression of peripheral nociceptor sensitization central nervous system hyperexcitability. Since it acts topically, even chronic use cannot raise the serum levels to nay significant levels, and it thus has a good safety profile. Studies conducted recently suggest that other than postherpetic neuralgia, the lidocaine patch is effective for other chronic neuropathic pain conditions also (Argoff, 2000). The topical application of 3.3% doxepin, or combination of 3.3% doxepin/0. 025% capsaicin produces good and more rapid analgesia (McCleane, 2000.) Transdermal fentanyl Patients with cancer pain frequently have difficulty in swallowing. Transdermal fentanyl may be a good alternative for such patients (Grond et al., 1997). The patch, which is applied every 72 hours, releases fentanyl through the skin at a rate of 25-100μg/hour. The dose may be increased if the analgesia does not last for 72 hours (Grond et al., 1997). The adverse effects are the same as that of morphine, although constipation is less (Dellemijn, van Duijn, Vanneste, n.d) In chronic non-malignant pain, the use of transdermal fentanyl is still debated. In patients with low back pain who are already taking oral morphine, the available data shows that transdermal fentanyl can give similar or improved pain control in 50% of the patients (Jeal & Benfield, 1997). In another study, intravenous fentanyl provided a temporary relief in patients with neuropathic pain. At least 27% of these patients had good prolonged pain control and they could tolerate the side effects well (Nurmikko, 1998). Spinal cord stimulation Two methods are used to perform spinal cord stimulation. In one method, a wire electrode is threaded into the epidural space and moved cranially to the correct level. In the other method, a laminectomy or laminotomy is used to suture a plate electrode to the dura. By inserting a temporary stimulating electrode percutaneously and attaching this to a portable external generator, an initial trial stimulation can be performed. Spinal cord stimulation is however, expensive (Nurmikko, 1998). Initially, it was though that spinal cord stimulation blocked the propagation of painful nerve impulses and the gate theory of pain transmission was used to explain the mechanism. Currently, many other mechanisms are also believed to play a role. Spinal cord stimulation activates spinal pain inhibiting circuits, especially those involved in GABAergic, and possibly adenosine dependent transmission (Lundeberg, 1996; Cui et al., 1997). Others suggest a cerebral level action (Hautvast et al., 1997). Experimental and human studies have shown that spinal cord stimulation induces peripheral vasodilatation (Croom, 1997.) The results of spinal cord stimulation are promising. Good reduction of pain has been reported in failed back surgery syndrome and neuropathic pain of peripheral origin, as well as in chronic angina and peripheral vascular disease (Turner et al., 1995; Eliasson et al., 1996; Kumar et al., 1997). One small placebo controlled design study has reported that spinal cord stimulation relieved the pain in diabetic polyneuropathy in two years (Nurmikko, 1998). Spinal pumps (or pain pumps) A pump implanted by a surgical procedure, pumps pain relieving drugs (like morphine, bupivacaine) into the intrathecal space around the spinal cord. A pump reservoir in the skin stores medication, which is added at regular intervals. Pain from failed back surgery syndrome, painful spasticity in multiple sclerosis etc may benefit from spinal pumps. Surgical treatment Lew et al., 2001 reviewed retrospectively reviewed 147 lower extremity peripheral nerve procedures in 114 patients with chronic lower extremity neuropathic pain. They reviewed whether transection and containment (for crush, stretch, and chronic transection injuries), transection and containment with peripheral nerve stimulation (for those with more chronic presentations), and revision neurolysis (for patients with adhesive neuralgia) could reduce pain and improve function. The results revealed that 52 (46%) patients could improve their work status after these procedures. Among all injuries in humans, paraplegia due to spinal cord trauma is considered to be the most devastating. In addition, 10-30% of these patients have the syndrome of persistent, incapacitating, posttraumatic neuropathic chronic pain. One treatment modality that is found useful in this condition is the Dorsal Root Entry Zone lesion (DREZ) operation, which ablates the dorsal horn of deafferented cord segments that generates pain. Different modalities like radiofrequency (RF), laser, ultrasound, and microsurgical DREZotomy technique (MDT) are used in the DREZ operation (Spaic et al., 2005.) Pain management programmes Though numerous advances have taken place in the management of pain, many patients with chronic pain have no relief from their symptoms, and in addition, have psychological distress, disability, and are dependent on family members and social services (Nurmikko, 1998). Pain management programmes help such patients to cope with their pain, better their physical performance, and change their attitudes, beliefs, and behavior in relation with respect to their pain (Nurmikko, 1998). There are various types of pain management programmes but group cognitive behavioral therapy is more commonly used. Both inpatient and outpatient programmes are used and are effective. However, inpatient treatment has been shown to give better results (Nurmikko, 1998). Some of the components of the programme include progressive muscular relaxation therapy, goal setting and pacing, group cognitive therapy, education about physiology and pain pharmacology, and progressive supervised physiotherapy exercises (Nurmikko, 1998). Therapeutic Nerve Blocks “A nerve block is an injection of an anesthetic directly in the area of the affected nerve. The purpose of a nerve block in treating neuropathic pain is to interrupt transmission of the pain signal to the brain. If the pain signal does not get to the brain, then pain is not actually felt or perceived by the patient”(Rashbaum, 2001.) Short-term relief of pain is obtained by giving injections into various problem-causing locations like dorsal roots, trigger points, sympathetic nervous system, peripheral nerves, trigger points, and plexi (Rashbaum, 2001). Medications that are injected include opioids, which give a strong, short-term relief of pain, local anesthetics for chronic pain, and steroid injections to decrease the inflammation and irritation, and thus, decrease pain (Rashbaum, 2001). In order to guide the specialist to insert the needle into the exact location, fluoroscopy is usually used. The frequency of the therapeutic nerve blocks depend on the severity of the pain, and how well the patient responds to the injections (Rashbaum, 2001) Transcutaneous electrical nerve stimulation (TENS) unit or electrotherapy TENS involves the placement of an external device with electrodes that applies low-voltage electricity over the skin. TENS units have been found to be effective in moderate to moderately severe acute to subacute pain. In some patients, it is effective for chronic pain also (Rashbaum, 2001.) Deep brain stimulation Owen et al., 2007 studied the effects of deep brain stimulation on forty-seven patients who were suffering from different intractable neuropathic pain syndromes like: post-stroke neuropathic pain, phantom limb pain, post-herpetic neuralgia, anesthesia dolorosa, brachial plexus injury and neuropathic pain secondary to neural damage from a variety of causes. They performed DBS of the sensory thalamus and the periventricular and peri-aqueductal grey area (PVG/PAG) complex. Based on their observations after the procedure, they concluded that DBS is most effective for phantom limb syndromes, head pain and anesthesia dolorosa. However, in peripheral neuropathic pain including pain after amputation and facial pain, there is only weak positive evidence. The results are equivocal and further comparative trials are required for the use of DBS in central post-stroke pain (CPSP) (Cruccu et al., 2007). The complications of DBS include: lead fractures, wound infection, post-operative burr hole site erosion, and intra-operative seizure (Cruccu et al., 2007). Motor Cortex Stimulation (MCS) MCS is useful in 50 to 60% of patients with CPSP and central or peripheral facial neuropathic pain, with only a little risk of complications. For any other neuropathic condition, there is not sufficient (Cruccu et al., 2007). Some reported complications include: seizures, malfunction, wound infection, pain, sepsis, and extradural hematoma (Cruccu et al., 2007). Repetitive Transcranial Magnetic Stimulation (rTMS) Repetitive Transcranial Magnetic Stimulation is performed using a figure-of-eight coil and high frequency (5 to 20 Hz) to the motor cortex. The evidence is moderate for this modality to offer relief in CPSP and several other neuropathic pain conditions. However, the effect of rTMS is modest and short-lasting, and thus, it should not be used as the main treatment in chronic neuropathic pain. It may be considered in case of short-lasting pains or to identify suitable candidates for an epidural implant (MCS) (Cruccu et al., 2007.) Recent treatments Some of the newer discoveries in various stages of development include: acetylcholine modulators, adenosine receptor agonists, cytokine inhibitors etc (Gilron & Coderre, 2007). Gene-related therapies Liu et al., 2004, built a “replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67).” Their aim was to determine if “spinal release of -amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI.” Their experiments were able to establish that “HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.” References Argoff CE, 2000. New Analgesics for Neuropathic Pain: The Lidocaine Patch. Clin J Pain. 16 Suppl (2): S62-S66 Butera, JA, 2007. Current and Emerging Targets To Treat Neuropathic Pain. J. Med. Chem. 50(11): 2543-2546. Bouhassira, D, 2001. Neuropathic pain: the clinical syndrome revisited. Acta neurol. belg. 101: 47-52. Canavera S, Bonicalzi V, 1996. Lamotrigine control of central pain. Pain. 68:179–181. Cui J-G, O’Connor WT, Ungerstedt U, Linderoth P, Meyerson BA, 1997. 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