Pain, neuropathic

Opioids are drugs that have morphine-like actions and the name comes from the source of morphine and opium, the opium poppy, Papaver somniferum. Opium itself is a mixture of substances that occur in the sap of the opium poppy. 

The actions of all opioids can be blocked by naloxone, which is used in cases of overdose. 

The effects of opioids on the central nervous system are to produce analgesia (particularly effective in chronic or acute pain of a constant nature), elevation of mood (euphoria), respiratory depression (occurs at therapeutic doses), cough suppression, nausea and vomiting and miosis (pin-point pupils). 

Other effects include reduction in tone and motility of the gastrointestinal tract, producing constipation, and the release of histamine from mast cells, causing local pain and itching at the injection site. Histamine released systemically may induce bronchoconstric-tion, bradycardia and hypotension. Tolerance and dependence are not usually a problem in clinical use. 

Other opioid analgesics are compared to morphine in Table 12.7. 

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Antiepileptics are used in neuropathic pain resulting from lesions to the peripheral (e.g., diabetes, heipes) or central nervous system (e.g., stroke). Such syndromes have been attributed to ectopic activity in sensitized nociceptors from regenerating nerve sprouts, recruitment of previously silent nociceptors, and/or spontaneous neuronal activity. This may result in sensitization... 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Antidepressants are used in neuropathic pain and migraine prophylaxis. Tricyclics require monitoring of plasma drug concentrations to achieve optimal effect... 

Neuropathic pain Endocannabinoid levels are elevated in FAAH inhibitors... 

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

Tanelian DL, Brose WG (1991) Neuropathic pain can be relieved by drugs that are use-dependent sodium channel blockers lidocaine, carbamazepine, and mexiletine. Anesthesiology 74 949-951... 

Neuropathic pain is initiated or caused by a primary lesion in the peripheral or central nervous system. The causative agent may be trauma, nerve-invading cancer, herpes zoster, HIV, stroke, diabetes, alcohol or other toxic substances. Neuropathic pain is refractory to most analgesic drugs. Altered sodium channel activity is characteristics of neuropathic pain states. 

Devor M (2006) Sodium channels and mechanisms of neuropathic pain. J Pain 7(1 Suppl 1) S3—SI2... 

The a28 subunit 1 and 2 bind gabapentin with high affinity. This interaction may be causally related to its antiepileptic and neuropathic pain alleviating property. 

Gabapentin and pregabalin are prescribed in certain epileptic diseases such as absence epilepsy and in neuropathic pain. Their therapeutic target for pain suppression is the a2S-l subunit. 

Schaddelee MP, Collins SD, DeJongh J, de Boer AG, Ijzerman AP, Danhof M. Pharmacokinetic/pharmacodynamic modelling of the anti-hyperalgesic and antinociceptive effect of adenosine A1 receptor partial agonists in neuropathic pain. Eur J Pharmacol 2005 May 9 514(2-3) 131-40. 

Distal sensory neuropathy AIDS Subacute or chronic Distal sensory loss and neuropathic pain depressed or absent ankle reflexes Immune dysfunction macrophage-mediated axonal injury... 

Antiretroviral toxic neuropathy Any stage Subacute rarely acute with lactic acidosis Distal sensory loss and neuropathic pain Toxic neuropathy mitochondrial damage... 

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

Epidermal nerve fiber analysis by immunocytochemical techniques using the panaxonal marker protein gene product 9.5 (PGP 9.5) allows the study of epidermal innervation by small fiber C and A5 nerve fibers (McCarthy et al. 1995 Holland et al. 1997). Studies of skin biopsies of HIV infected patients with DSP or ATN showed reduction in the number of epidermal fibers in distal areas of the lower extremities with an inverse correlation between neuropathic pain intensity and epidermal nerve fiber density (Polydefkis et al. 2002) (Fig. 4.3). There were also fewer epidermal fibers in HIV seropositive patients without clinical evidence of neuropathy, suggesting that HIV infection may be associated with the loss of cutaneous innervation even before the onset of sensory symptomatology (McCarthy et al. 1995). 

Herzberg U, Sagen J (2001) Peripheral nerve exposure to HIV viral envelope protein gpl20 induces neuropathic pain and spinal gliosis. J Neuroimmunol 116(l) 29-39 Herzmann C, Johnson MA et al (2005) Long-term effect of acetyl-L-carnitine for antiretroviral toxic neuropathy. HIV Clin Trials 6(6) 344-350... 

Sweitzer SM, Hickey WF et al (2002) Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system potential relationship to neuropathic pain. Pain 100(1-2) 163-170... 

Verma S, Estanislao L et al (2005) HIV-associated neuropathic pain epidemiology, pathophysiology and management. CNS Drugs 19(4) 325-334 ViUa A, Forest V et al (1987) Autonomic neuropathy and HIV infection. Lancet 2(8564) 915... 

Wagner R, Myers RR (1996) Endoneurial injection of TNF-alpha produces neuropathic pain behaviors. Neuroreport 7(18) 2897-2901... 

Wallace VC, Blackbeard J et al (2007a) Pharmacological, behavioural and mechanistic analysis of HIV-1 gpl20 induced painful neuropathy. Pain 133(l-3) 47-63 Wallace VC, Blackbeard J et al (2007b) Characterization of rodent models of HIV-gpl20 and anti-retroviral-associated neuropathic pain. Brain 130(Pt 10) 2688-2702 Wechsler AF, Ho DD (1989) Bilateral Bell s palsy at the time of HIV seroconversion. Neurology 39(5) 747-748... 

White FA, Jung H et al (2007) Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci USA 104(51) 20151-20158... 

Abbadie C (2005) Chemokines, chemokine receptors and pain. Trends Immunol 26 529-534 Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, DeMartino JA, MacIntyre DE, Forrest MJ (2003) Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci USA 100 7947-7952 Ahn DK, Lee KR, Lee HJ, Kim SK, Choi HS, Lim EJ, Park JS (2005) Intracistemal administration of chemokines facditated formalin-induced behavioral responses in the orofacial area of freely moving rats. Brain Res Bull 66 50-58... 

Westmoreland SV, Rottman JB, Williams KC, Lackner AA, Sasseville VG (1998) Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis. Am J Pathol 152 659-665 White FA, Jung H, Miller RJ (2007) Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 104 20151-20158... 

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