The Pharmacological management of neuropathic pain: A review

Dr Gary McCleane MD FFARCSI, Consultant Anaesthetist, Pain Clinic, Craigavon Area Hospital
gary@mccleane.freeserve.co.uk

See also related article on Pain and Dissociation



Key points    

 Introduction

 Tissue injury is usually accompanied by pain and is described as neuropathic if the initiating injury occurs to neural tissue.  After injury occurs, symptoms are initially experienced distal to the site of injury: by  contrast in non-neuropathic pain (nociceptive pain) symptoms are apparent, at least initially, at the site of injury. With time the margins between these types become blurred and each may coexist with the other.  The consequence of neural injury is change in neural function both at the site of injury and proximal to it with the symptoms produced being manifestations of neural over or under activity. Typical features of neuropathic pain, regardless of the causal injury, include shooting / lancinating pain, burning pain, paraesthesia / dysaesthesia, numbness and allodynia (pain produced by a normally non-painful stimulus).

In addition to differing symptoms experienced with neuropathic and nociceptive pain, there are differences in those therapeutic agents which can produce pain relief.  For example, it is accepted that nociceptive pain may be relieved by morphine and non-steroidal anti-inflammatory drugs (NSAIDs). However, with neuropathic pain some studies suggest analgesia with morphine (1,2)  and NSAIDs (3,4) , while others demonstrate no analgesia with morphine (5, 6)  or NSAIDs (7,8)

The aim of this article is to highlight current therapeutic options for the treatment of neuropathic pain.

Capsaicin

It has been recognised for almost 150 years that the topical application of extracts of the capsicum pepper can produce pain relief (9) .  It is now recognised that the active pain killing constituent of the chili pepper is capsaicin, which when repeatedly applied topically in appropriate concentration causes reversible depletion of the neurotransmitter substance P (SP) from the sensory nerve endings (10)  and hence pain relief, which may take several weeks to occur.  Topical application of capsaicin has been shown to reduce the pain of a variety of conditions, including post herpetic neuralgia (11 - 13) , painful diabetic neuropathy (14 - 16) , chronic distal painful polyneuropathy (17) ,  surgical neuropathic pain (18) , post mastectomy syndrome (19)  and osteoarthritis ( 20 - 23) .  The major side effect is that of burning discomfort which may lead to poor patient compliance.  The addition of glyceryl trinitrate (GTN) to capsaicin reduces the burning discomfort associated with application (24,25)  and may improve compliance.  GTN is also known to have an anti-inflammatory effect (26, 27)  and this may augment the analgesia from the capsaicin.

Tricyclic antidepressants

It is widely accepted that oral tricyclic antidepressants (TCAs) have an analgesic effect in neuropathic  pain (28, 29) with evidence of efficacy existing for amitriptyline (30 - 34) ,  imipramine (35), desimipramine (36 - 38)  and clomipramine (39, 40) .  This analgesic effect is independent of their antidepressant effect (41)  and may be dose related (42,43) .  TCAs have an effect of 5 hydroxytriptamine release (44) , the noradrenergic pathways (45)  and a sodium channel blocking effect (46), the later effect being shared by the local anaesthetic and anticonvulsant groups.

Unfortunately, the undoubted analgesic effect of the TCAs is tempered by their side effect profiles with somnolence and dry mouth being the predominant side-effects.  Recent work has highlighted a potential analgesic effect of topical doxepin, a TCA, in neuropathic pain (47,48) .  The topical application of doxepin is associated with few side effects, and particularly central side-effects.  Animal work has suggested a potential peripheral action of TCAs (49, 50)  and may explain the analgesis seen in human studies.

   

Anticonvulsants

It has long been appreciated that there a similarities between epilepsy and neuropathic pain (in 1885 Trousseau described trigeminal neuralgia as "epileptiform neuralgia 51) ) and that drugs that are effective in reducing seizure frequency may also have an analgesic effect in neuropathic pain (52, 53) .  The first report of analgesia with an anticonvulsant in neuropathic pain was with phenytoin in 1942 (54).  Subsequent randomised controlled trials (RCTs) has confirmed this case report evidence with phenytoin (55, 56) .  In 1962 case report evidence of analgesia with carbamazepine emerged (57) , with subsequent support from RCTs in trigeminal neuralgia (58) and painful diabetic neuropathy (59) .  Carbamazepine remains the most frequently used anticonvulsant for neuropathic pain (60)

Anecdotal evidence points to a similar analgesic effect with lamotrigine (61 - 64) , although the evidence from the small number of RCTs so far reported is mixed (65, 66) . The analgesia from lamotrigine may be dose related and studies reporting no analgesia used low dosing regimes of this drug.

Gabapentin, a structural analogue of the inhibitory neurotransmitter gamma amino butyric acid (GABA), which paradoxically is thought not to exert its effect on GABA receptors (67) , has recently been demonstrated to reduce neuropathic  pain (68 - 73) ,  and in particular post herpetic neuralgia (74)  and painful diabetic neuropathy (75) , both conditions being archetypal neuropathic pain conditions.  The potential advantage of lamotrigine and gabapentin over carbamazepine are their more favourable side effect profiles (76)

When oral dose titration is not possible then parenteral administration may be necessary.  Intramuscular fosphenytoin (a water soluble ester pro-drug of phenytoin, lacking its infusion related side-effects) produces analgesia where neuropathic pain is present (81) .  Intravenous infusions of phenytoin and fosphenytoin both have a similar analgesic effect with the added advantage of relief that extends beyond the period of infusion and the intravascular half-life of the drug (82, 83) .

Despite a common effect (reduction in seizure frequency and analgesia), anticonvulsants differ in their mode of action.  Phenytoin has a sodium channel blocking effect (77)  while lamotrigine has an effect on voltage gated cation channels (78)  and glutamate release (79) , while gabapentin appears to exert its action via the alpha delta 2 sub unit of the calcium channel (80) .  The clinical consequence of these differing modes of action is that a failed trial with one anticonvulsant does not mean that another in this class will not work.

Baclofen

Baclofen, like gabapentin, is structurally similar to the inhibitory amino acid gamma amino butyric acid (GABA) and yet seems to have a mechanism of action that differs to that of GABA (84, 85) .  It is known to depress release of the excitatory neurotransmitters glutamate and aspartate (86, 87) .   Isolated studies suggest an analgesic effect in trigeminal neuralgia (88, 89) .

CCK Antagonists

The causes of incomplete analgesia with opiates in neuropathic pain are many.  Among them are elevation of the anti-opioid peptide cholecystokinin (CCK) (90 - 92) .  Neural injury produces an elevation in plasma CCK levels (93) , and if a CCK antagonist is administered, then opiate sensitivity in neuropathic pain may return.  The obsolete anti-ulcer drug proglumide is a non-specific CCK antagonist (94)  and has been shown to augment the analgesic effect of sustained release morphine in neuropathic pain (95, 96) .  As well as reducing the analgesic effect of opiates, CCK is also elevated with chronic opiate administration, and hence more opiate is required to achieve the same level of analgesia with the passage of time (tolerance) (97 - 103) .  CCK antagonists such as proglumide can reverse this tolerance.  It may therefore be that opiates can be used to treat chronic neuropathic pain when co-administered with a CCK antagonist, although the debate will continue as to whether a dose limit be put on the sustained release morphine preparation.

Membrane Stabilisers

For many years intravenous infusions of local anaesthetics have been used in the management of both acute and chronic pain: the analgesia of IV novocaine was described in 1943 (104) .    Despite much anecdotal evidence of analgesia with IV lignocaine (105 - 8)  there are few RCTs to verify this effect.  It does seem that a short term infusion (e.g. 24 hours) may give relief in some patients for a sustained period (weeks to months).  Parenteral local anaesthetics seem to suppress the activity of spontaneously active fibres  in neuromas (109), , depresses C - afferent fibre evoked activity in the spinal cord (110)  and silence dorsal root ganglion discharge without blocking nerve conduction (111) .

Parenteral administration of local anaesthetics may not always be feasible and there is  some evidence to suggest that the oral equivalent mexiletene may also have an analgesic effect (112 ) .

Ketamine

Ketamine, a N-methyl D-aspartate (NMDA) receptor antagonist can have an analgesic effect in neuropathic pain (113 - 4).  Its use is associated with side-effects that limit its use, but recent work has suggested an opiate potentiating effect that may be apparent at otherwise sub-therapeutic doses (115) .

Nerve blocks

The perineural injection of drugs seems to produce pain relief in some patients with neuropathic pain for varying lengths of time.  Local anaesthetic injection may give only short term relief.  However, the addition of corticosteroid may lengthen the pain relief produced. Steroids reduce inflammation by reducing prostaglandin synthesis (116 ) , suppress ectopic discharge (117) , have C fibre membrane stabilising effects (118)  and stabilise the dorsal horn cell (119)  and any or all of these effects may contribute to the pain relief produced.  With the example of epidural steroid administration there is mixed evidence with some reports claiming benefit (120)  , while others suggest less significant benefit in terms of extent and duration of relief (121 - 2)

Clonidine

The alpha adrenoreceptor agonist clonidine has been used for many years as an antihypertensive agent.  When administered by the epidural or intrathecal route it has an effect on the descending noradrenergic pathways (123 - 4)  which produces analgesia (125 -  8) .  Unfortunately oral administration is not associated with such relief.

Discussion

While many other agents may be used in treating neuropathic pain, their use is not verified by appropriate studies.  It is hoped that the rational use of drugs increases the chance of achieving analgesia in the patient with neuropathic pain.  However, when one considers the "numbers needed to treat" (N.N.T.), that is the numbers of patients needing to take the drug to achieve 50% reduction of that symptom in one patient, for the medication used in neuropathic pain it is clear that it is always greater than 2.5 (28,52) .  Consequently, no one therapeutic intervention is guaranteed of success.  This is similar to drugs used in nociceptive pain where the N.N.T. varies from 3.1 with paracetamol 500mg / codeine 60mg, to 3.6 with paracetamol 600 or 500mg, to 9.1 with codeine 60mg (129) .  Consequently it may often be necessary to work ones way through a list of treatment options before analgesia is achieved.  Inevitably any relief produced may be tempered by the associated side-effects of that drug so that improvement in quality of life (pain reduction, mood elevation, increased mobility, better sleep with minimal side effects from treatment) is the therapeutic goal.  Poly pharmacy is a real danger, with patients staying on medication in hope of relief when none is actually apparent.  Trials of medication for a defined period of time with assessment before and after may be more appropriate.

Pharmacological management will produce the desired analgesia in some, but not all, patients.  In those who fail to respond, other modalities of treatment may be considered, ranging from behaviour modification and fostering of coping skills to the more major invasive medical techniques.  It is still reassuring, however, to realise that in the future we have the prospect of additional agents which may or may not prove useful analgesics in neuropathic pain.  These include agents with more specific sodium channel blocking effects, calcium channel blockers and new generation anticonvulsants and capitalise on the major expansion in knowledge generated from the work of the basic scientists.

  It is hoped that this paper highlights the current outpatient therapeutic options and demonstrates a rational approach to the management of the patient with neuropathic pain.

   

References

 

1.  Kupers RC, Konings H, Adriaensen H, Gybels JM.  Morphine differentially affects sensory and affective pain ratings in neurogenic and idiopathic forms of pain.  Pain 1991; 47: 5 - 12.

2.  Rowbotham MC, Reisner-Keller LA, Fields HL.  Both intravenous lidocaine and morphine reduce the pain of post herpetic neuralgia.  Neurology 1991; 41: 1024 - 8.

3.  Cohen KL, Harris S.  Efficacy and safety of non-steroidal anti-inflammatory drugs in the therapy of diabetic neuropathy.  Arch Intern Med 1987; 147: 1442 - 4.

4.  Benedittis GD, Besana F, Lorenzetti A.  A new topical treatment for acute herpetic neuralgia and post-herpetic neuralgia: the aspirin / diethyl ether mixture.  An open label study plus a double-blind controlled clinical trial.  Pain 1992; 48: 383 - 90.

5.  Arner S, Meyerson BA.  Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain.  Pain 1988; 33: 11 - 23.

6.  Eide PK, Jorum E, Stubhaug A.  Relief of post herpetic neuralgia with the N-methyl-D-aspartate receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo.  Pain 1994; 58: 347 - 54.

7.  Weber H, Holme I, Amlie E.  The natural course of acute sciatica with nerve root symptoms in a double-blind placebo-controlled trial evaluating the effect of piroxicam.  Spine 1993; 11: 1433 - 8.

8.  Max MB, Schafer SC, Culnane MS, Dubner R, Gracely RH.  Association of pain relief with drug side-effects in post herpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo.  Clin Pharmacol Ther 1988; 43: 363 - 71.

9.  Turnbull A.  Tincture of capsicum as a remedy for chilblains and toothache.  Dublin Medical Press 1850; 6: 95.

10.  Fitzgerald M.  Capsaicin and sensory neurones - a review.  Pain 1983; 15: 109 - 30.

11.  Watson CPN, Evans RJ, Watt VR.  Post-herpetic neuralgia and topical capsaicin.  Pain 1988; 33: 333 - 40.

12.  Watson CPN, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E.  A randomized vehicle-controlled trial of topical capsaicin in the treatment of post herpetic neuralgia.  Clinical Therapeutics 1993; 15: 510 - 26.

13.  Bernstein JE, Korman NJ, Bickers DR, Dahl MV, Millikan LE.  Topical capsaicin treatment of chronic postherpetic neuralgia.  J Am Acad Dermatol 1989; 21: 265 - 70.

14.  Tandan R, Lewis GA, Krusinski PB, Badger GB, Fries TJ.  Topical capsaicin in painful diabetic neuropathy.  Diabetes Care 1992; 15: 8 - 13.

15.  The Capsaicin Study Group.  Treatment of painful diabetic neuropathy with topical capsaicin.  A multicentre, double-blind, vehicle-controlled study.  Arch Intern Med 1991; 151:  2225 - 9.

16.  Capsaicin Study Group.  Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy.  Diabetes Care 1992; 15:  159 - 65.

17.  Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O'Brien PC.  Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy.  Pain 1995; 60: 163 - 8.

18.  Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, Wender DB, Rowland KM, Molina R, Cascino TL, Vukov AM, Dhaliwal HS, Ghosh C.  Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients.  J Clin Oncol 1997; 15: 2974 - 80.

19.  Watson CPN, Evans RJ.  The post mastectomy pain syndrome and topical capsaicin: a randomized trial.  Pain 1992; 51: 375 - 9.

20.  Schnitzer T, Morton C, Coker S.  Topical capsaicin therapy for osteoarthritis pain: achieving a maintenance regime.  Seminars in Arthritis and Rheumatism 1994; 23: 34 - 40.

21.  Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, Albert D, Renold F.  Treatment of arthritis with topical capsaicin: a double-blind trial.  Clin Therapeutics 1991; 13: 383 - 95.

22.  Altman RD, Aven A, Holmburg CE, Pfeifer LM, Sack M, Young GT.  Capsaicin cream 0.025% as mono therapy for osteoarthritis: a double-blind study.  Seminars in Arthritis and Rheumatism 1994; 23: 25 - 33.

23.  McCarthy GM, McCarty DJ.  Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands.  J Rheumatol 1992; 19: 604 - 7.

24.  McCleane GJ, McLaughlin M.  The addition of GTN to capsaicin cream reduces the discomfort associated with application of capsaicin alone.  A volunteer study.  Pain 1998;78:149 - 51.

25.  McCleane GJ.  The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: a randomised, double-blind, placebo controlled study.

Under  review.

26.  Berrazueta JR, Losada A, Poveda J, Ochoteco A, Riestra A, Salas E, Amado JA.  Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerine.  A double blind study.  Pain 1996; 66:  63 - 7.

27.  Berrazueta JR, Poveda JJ, Ochoteco J, Amado JA, Puebla F, Salas E, Sarabia M.  The anti-inflammatory and analgesic action of transdermal glyceryl trinitrate in the treatment of infusion related thrombophlebitis.  Postgrad Med J 1993; 69: 37 - 40.

28.  McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA.  A systematic review of antidepressants in neuropathic pain.  Pain 1996; 68: 217 - 27.

29.  McQuay HJ, Moore RA.  Antidepressants and chronic pain.  BMJ 1997; 314: 763 - 4.

30.  Watson CPN, Evans RJ.  A comparative trial of amitriptyline and zimelidine in post-herpetic neuralgia.  Pain 1985; 23: 387 - 94.

31.  Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam relieves postherpetic neuralgia.  Neurology 1988; 38: 1427 - 32.

32.  Watson CPN, Evans RJ, Reed K, Merskey H, Goldsmith L, Warsh J.  Amitriptyline versus placebo in postherpetic neuralgia.  Neurology 1982;32: 671 - 3.

33.  Leijon G, Boivie J.  Central post-stroke pain - a controlled trial of amitriptyline and carbamazepine.  Pain 1989; 36: 27 - 36.

34.  Watson CPN, Chipman M, Reed K, Evans RJ, Birkett N.  Amitriptyline versus maprotiline in postherpetic neuralgia: a randomized, double-blind, cross-over trial.  Pain 1992; 48: 29 - 36.

 35.  Kvinesdal B, Molin J, Froland A, Gram LF.  Imipramine treatment of painful diabetic neuropathy.  JAMA 1984; 251: 1727 - 30.

36.  Kishore-Kumar R, Max MB, Schafer SC, Gaughan AM, Smoller B, Gracely RH, Dubner R.  Desipramine relieves postherpetic neuralgia.  Clin Pharmacol Ther 1990; 47: 305 - 12.

37.  Max MB, Kishore-Kumar R, Schafer SC, Meister B, Gracely RH, Smoller B, Dubner R.  Efficacy of desimipramine in painful diabetic neuropathy: a placebo controlled trial.  Pain 1991; 45: 3 - 9.

38.  Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R.  Effects of desimipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.  N Eng J Med 1992; 326: 1250 - 6.


39.  Sindrup KH, Gram LF, Skjold T, Grodum E, Brosen K, Beck-Nielsen.  Clomipramine vs Desipramine vs placebo in the treatment of diabetic neuropathy symptoms.  A double-blind cross-over study.  Br J Clin Pharmacol 1990; 30: 683 - 91.

40.  Langohr HD, Stohr M, Petruch F.  An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies.  Eur Neurol 1982; 21: 309 - 17.

41.   Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, Smoller B, Dubner R.  Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood.  Neurology 1987; 37: 589 - 96.

42.  McQuay HJ, Carroll D, Glynn CJ.  Dose-response for analgesic effect of amitriptyline in chronic pain.  Anaesthesia 1993; 48: 281 - 5.

43.  Sindrup SH, Gram LF, Skjold T, Froland A, Beck-Nielsen.  Concentration - response relationship in imipramine treatment of diabetic neuropathy symptoms.  Clin Pharmacol Ther 1990; 47: 509 - 15.

44. Charney DS, Heninger GR, Sternberg DE.  Serotonin function and mechanisms of action of antidepressant treatment.  Arch Gen Psychiatry 1984; 41: 359 - 65.  

45.  Ansuategui M, Naharro L, Feria M.  Noradrenergic and opioidergic influences on the antinociceptive effect of clomipramine in the formalin test in rats.  Psycho pharmacology 1989; 98: 93 - 6.  

46.  Pancrazio JJ, Kamatachi GL, Roscoe AK, Lynch C.  Inhibition of neuronal Na+ channels by antidepressant drugs.  J Pharmacol Exp Ther 1998; 284:  208 - 14.

47.  McCleane GJ.  Topical doxepin hydrochloride reduces neuropathic pain: a randomised, double-blind, placebo controlled study.  The Pain Clinic 1999; 12: 47 - 50.

48.  McCleane GJ.  Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic benign neuropathic pain: a randomised, double-blind, placebo controlled study.  In Press British Journal of Clinical Pharmacology

49.  Sawynok J, Esser MJ, Reid AR.  Peripheral antinociceptive actions of desimipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat.  Pain 1999; 82: 149 - 58.

50.  Sawynok J, Reid AR, Esser MJ.  Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine.  Pain 1999; 80: 45 - 55.

51.  Trousseau A.  De la nevralgie Epileptiforme.  Clin Med Hotel Dieu 1885; 2: 33 - 44.

52. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A.  Anticonvulsant drugs for management of pain: a systematic review.  BMJ 1995; 311: 1047 - 52.

53.  Kingery WS.  A critical review of controlled trials for peripheral neuropathic pain and complex regional pain syndrome.  Pain 1997; 73: 123 - 39.

54.  Bergouignan M.  Cures heureuses de nevralgies faciales essentielles par le diphenylhydantoinate de soude.  Rev Laryngol Otol Rhinol 1942; 63: 34 - 41.

55.  Chadda VS, Mathur MS.  Double blind study of the effects of diphenylhydantoin sodium on diabetic neuropathy.  J Assoc Physicians India 1978; 26:  403 - 6.

56.  Saudek CD, Werns S, Reidenberg MM.  Phenytoin in the treatment of diabetic symmetrical polyneuropathy.  Clin Pharmacol Ther 1977; 22: 196 - 9.

57.  Blom S.  Trigeminal neuralgia; its treatment with a new anticonvulsant drug (G32883).  Lancet 1962; i: 839.

58.  Campbell FG, Graham JG, Zilkha KJ.  Clinical trial of carbazepine (Tegretol) in trigeminal neuralgia.  J Neurol Neurosurg Psychiat 1966; 29: 265 - 7.

59.  Rull J, Quibrera R, Gonzalez-Millan H, Castenada LO.  Symptomatic treatment of peripheral diabetic neuropathy with carbamazepine: double-blind crossover study.  Diabetologia 1969; 5: 215 - 20.

60.  McCleane GJ.  Anticonvulsants - epilepsy or pain?  In Press Ulster Medical Journal

61.  Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, Favale E.  Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia.  Neurology 1997; 48: 1714 - 7.

62.  McCleane GJ.  A prospective audit of the use of lamotrigine in 300 chronic pain patients.  The Pain Clinic 1998; 11: 97 - 102.

63.  Canavero S, Bonicalzi V.  Lamotrigine control of central pain.  Pain 1996; 68: 179 - 81.

64.  McCleane GJ.  Lamotrigine can remove the pain associated with painful diabetic neuropathy.  The Pain Clinic 1998; 11: 69 - 71.

65.  McCleane GJ.  200mg daily of lamotrigine has no analgesic effect in neuropathic pain.: a randomised, double-blind, placebo controlled trial.  Pain 1999; 83: 105 - 7.

66.  Lamotrigine (Lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial.  Pain 1997; 73: 223 - 30.

67.  Brown JP, Boden P, Singh L, Gee NS.  Mechanisms of action of gabapentin.  Rev Contemp Pharmacother 1996; 7: 203 - 14.

68.  Houtchens MK, Richert JR, Sami A, Rose JW.  Open label gabapentin treatment for pain in multiple sclerosis.  Multiple Sclerosis 1997; 3: 250 - 3.

69.  Mellick GA, Seng ML.  The use of gabapentin in the treatment of reflex sympathetic dystrophy and a phobic disorder.  American Journal of Pain Management 1995; 5: 7 - 9.

70.  Mellick GA, Mellick LB.  Reflex sympathetic dystrophy treated with gabapentin.  Arch Phys Med Rehabil 1997; 78: 98 - 105.

71.  Rosner H, Rubin L, Kestenbaum A.  Gabapentin adjunctive therapy in neuropathic pain states.  The Clinical Journal of Pain 1996; 12: 56 - 8.

72.  Sist TC, Filadora VA, Miner M, Lema M.  Experience with gabapentin for neuropathic pain in the head and neck: report of ten cases.  Reg Anesth 1997; 22: 473 - 8.

73.  McGraw T, Stacey BR.  Gabapentin for treatment of neuropathic pain in a 12 year old girl.  The Clinical Journal of Pain 1998; 14: 354 - 6.

74.  Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L.  Gabapentin for the treatment of postherpetic neuralgia.  A randomized controlled trial.  JAMA 1998; 280:1837 - 42.

75.  Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Hes M, LaMoreaux L, Garofalo E.  Gabapentin for the treatment of painful neuropathy in patients with diabetes mellitus.  A randomized controlled trial.  JAMA 1998; 280:1831 - 6.

76.  Cohen AF, Ashby L, Crowley D, Land G, Peck AW, Miller AA.  Lamotrigine (BW430C), a potential anticonvulsant.  Effects on the central nervous system in comparison with phenytoin and diazepam.  Br J Clin Pharmac 1985; 20: 619 - 29.

77.  Lang DG, Wang CM, Cooper BR.  Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells.  J Pharmacol Exp Ther 1993; 266: 829 - 35.

78.  Lees G, Leach MJ.  Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neuroglial cultures from rat cortex.  Brain Research 1993;  612: 190 - 9.

79.  Teoh H, Fowler LJ, Bowery NG.  Effect of lamotrigine on the electrically - evoked release of endogenous amino acids from slices of dorsal horn of the rat spinal cord.  Neuropharmacol 1995; 34: 1273 - 8.

80.  Gee NS, Brown JP, Dissanayake VUK, Offord J, Thurlow R, Woodruff GN.  The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha delta 2 sub unit of a calcium channel.  The Journal of Biological Chemistry 1996; 271: 5768 - 76.

81.  McCleane GJ.  Intramuscular fosphenytoin relieves neuropathic pain: a randomised, double - blind, placebo controlled, crossover study. Under Review

82.  McCleane GJ.  Intravenous phenytoin infusion relieves acute neuropathic pain: a randomised, double-blind, placebo controlled study. Anesthesia & Analgesia  1999; 89: 985 - 8.

83.  McCleane GJ.  Intravenous fosphenytoin relieves neuropathic pain: a randomised, placebo - controlled trial. Under review

84.  Naik SR, Guidotti A, Costa E.  Central GABA agonists: comparison of muscimol and baclofen.  Neuropharmacology 1976; 15: 479 - 84.

85.  Davidoff RA, Sears ES.  The effects of lioresal on synaptic activity in the isolated spinal cord.  Neurology 1974; 24: 957 - 63.

86.  Potashner SJ.  Baclofen: effects on amino acid release.  Can J Physiol Pharmacol 1978; 56: 150 - 4.

87.  Potashner SJ.  Baclofen : effects on amino acid release and metabolism in slices of guinea pig cerebral cortex.  J Neurochem 1979; 32: 103 - 9.

88.  Fromm GH, Terrence CF, Chattha AS.  Baclofen in the treatment of trigeminal neuralgia: double-blind study and long - term follow up.  Ann Neurol 1984; 15: 240 - 4.

89.  Zakrzewska JM, Patsalos PN.  Drugs used in the management of trigeminal neuralgia.  Oral Surg Oral Med Oral Pathol 1992; 74: 439 - 50.

90.  Xu X-J, Hao J-X, Seiger A, Hughes J, Hokfelt T, Wiesenfeld-Hallin Z.  Chronic pain-related behaviours in spinally injured rats: evidence for functional alterations of the endogenous cholecystokinin and opioid systems.  Pain 1994; 56: 271 - 7.

91.  Wiesenfeld-Hallin Z, Xu X-J.  The role of cholecystokinin in nociception, neuropathic pain and opiate tolerance.  Regulatory Peptides 1996; 65: 23 - 8.

92.  Nichols ML, Bian D, Ossipov MH, Lai J, Porreca F.  Regulation of morphine anti allodynic efficacy by cholecystokinin in a model of neuropathic pain in rats.  J Pharmacol Exp Ther 1995; 275: 1339 - 45.

93.  Xu X-J, Puke MJC, Verge VMK, Wiesenfeld-Hallin Z, Hughes J, Hokfelt T.  Up-regulation of cholecystokinin in primary sensory neurones is associated with morphine insensitivity in experimental neuropathic pain in the rat.  Neuroscience Lett 1993; 152: 129 - 32.

94.  Hahne WF, Jensen RT, Lemp GF, Gardener JD.  Proglumide and benzotript: members of a different class of cholecystokinin receptor antagonists.  Proc Natl Acad Sci USA 1981; 78: 6304 - 8.

95.  McCleane GJ.  The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain.  Anesth Anal 1998; 87: 1117 - 20.

96.  McCleane GJ.  The cholecystokinin antagonist proglumide enhances the analgesic effect of morphine in chronic benign nociceptive and neuropathic pain.  The Pain Clinic 1998; 11: 103 - 7.

97.  Kellstein DE, Mayer DJ.  Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pre treatment.  Brain Research 1990; 516: 263 - 70.

98.  Hoffmann O, Wiesenfeld-Hallin Z.  The CCK-B receptor antagonist CI 988 reverses tolerance to morphine in rats.  NeuroReport 1994; 5: 2565 - 8.

99.  Dourish CT, Hawley D, Iversen SD.  Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718.  Eur J Pharmacol 1988; 147: 469 - 72.

100.  Dourish CT, O'Neill MF, Coughlan J, Kitchener SJ, Hawley D, Iversen SD.  The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat.  Eur J Pharmacol 1990; 176: 35 - 44.

101.  Idanpaan-Heikkila JJ, Guilbaud G, Kayser V.  Prevention of tolerance to the antinociceptive effects of systemic morphine by a selective cholecystokinin - B receptor antagonist in a rat model of peripheral neuropathy.  J Pharmacol Exp Ther 1997; 282: 1366 - 72.

102.  Tang J, Chou J, Iadarola M, Yang HYT, Costa E.  Proglumide prevents and curtails acute tolerance to morphine in rats.  Neuropharmacology 1984; 23: 715 - 8.

103.  Watkins LR, Kinscheck IB, Mayer DJ.  Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide.  Science 1984; 224: 395 - 6.

104.  Gordon RA.  Intravenous novocaine for analgesia in burns.  Can M A J 1943; 49: 478 - 9.

105.  Bartlett EE, Hutaserani O.  Xylocaine for the relief of postoperative pain.  Anesth Analg 1961; 40: 296 - 304.

106.  Kastrup J, Petersen P, Dejgard A, Angelo HR, Hilsted J.  Intravenous lidocaine infusion - a new treatment of chronic painful diabetic neuropathy.  Pain 1987; 28: 69 - 75.

107.  Edwards WT, Habib F, Burney RG, Begin G.  Intravenous lidocaine in the management of various chronic pain states.  Regional Anesth 1985; 10: 1 - 6.

108.  Tanelian DL, Brose WG.  Neuropathic pain can be relieved by drugs that are use - dependent sodium channel blockers: lidocaine, carbamazepine, and mexiletene.  Anesthesiology 1991; 74: 949 - 51.

109.  Chabal C, RussellLC, Burchiel KJ.  The effect of intravenous lidocaine, tocainide, and mexiletene on spontaneously active fibers originating in rat sciatic neuromas.  Pain 1989; 38: 333 - 8.

110.  Woolf CJ, Wiesenfeld-Hallin Z.  The systemic administration of local anaesthetics produces a selective depression of C - afferent fibre evoked activity in the spinal cord.  Pain 1985; 23: 361 - 74.

111.  Devor M, Wall PD, Catalan N.  Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction.  Pain 1992; 48: 261 - 8.

112.  Chabal C, Jacobson L, Mariano A, Chaney E, Britell CW.  The use of oral mexiletene for the treatment of pain after peripheral nerve injury.  Anesthesiology 1992; 76: 513 - 7.

113.  Eide PK, Jorum E, Stubhaug A, Bremnes J, Breivik H.  Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo.  Pain 1994; 58: 347 - 54.

114. Hoffmann V, Coppejans H, Vercauteren M, Adriaensen H.  Successful treatment of postherpetic neuralgia with oral ketamine.  Clin J Pain 1994; 10: 240 - 2.

115. Chapman V, Dickenson AH.  The combination of NMDA receptor antagonism and morphine produces profound antinociception in the rat dorsal horn.  Brain Res 1992; 573: 321 - 3.

116.  Smith AC, Brook IM.  Inhibition of tissue prostaglandin synthesis during third molar surgery: use of preoperative fenbrufen.  Br J Oral Max Surg 1990; 44: 251 - 3.

117.  Devor M, Govrin-Lippmann R, Raber P.  Corticosteroids suppress ectopic neural discharge originating in experimental neuromas.  Pain 1985; 22: 127 - 37.

118.  Johansson AJ, Hao J, Sjolund B.  Local corticosteroid application blocks transmission in normal nociceptive C-fibres.  Acta Anaesth Scand 1990; 34: 335 - 8.

119.  Hall ED.  Acute effects of intravenous glucocorticosteroids on cat spinal motor neurone electrical properties.  Brain Research 1982; 240: 186 - 90.

120.  Dilke TFW, Burry HC, Grahame R.  Extradural corticosteroid injection in management of lumbar nerve root compression.  BMJ 1973; 635 - 7.

121.  Koes BW, Scholten RJ, Mens JM, Bouter LM.  Efficacy of epidural steroid injections for low - back pain and sciatica: a systematic review of randomised clinical trials.  Pain 1995; 63: 279 - 88.

122.  Rosen CD, Kahanovitz N, Bernstein R, Viola K.  A retrospective analysis of the efficacy of epidural steroid injection.  Clinical Orthopaedics and Related Research 1987; 228: 270 - 2.

123.  Dahlstrom A, Fuxe K.  Evidence for the existence of mono amine containing neurones in the central nervous system. I.  Demonstration of mono amines in the cell bodies of brain stem neurones.  Acta Physiol Scan 1964; 62: 1 - 55.

124.  Dahlstrom A, Fuxe K.  Evidence for the existence of mono amine containing neurones in the central nervous system.  II.  Experimentally induced changes in the inter neuronal amine levels of bulbospinal neurone systems.  Acta Physiol Scan 1965; 64: 1 - 36.

125.  Coventry DM, Todd G.  Epidural clonidine in lower limb deafferentation pain.  Anesth Analg 1989; 69: 407 - 8.

126.  Spaulding TC, Fielding S, Venafro JJ, Lal H.  Antinociceptive activity of clonidine and its potentiation of morphine analgesia.  Eur J Pharmacol 1979; 58: 19 - 25.

127.  Eisenach JC, Rauck RL, Buzzanell C, Lysak SZ.  Epidural clonidine analgesia for intractable cancer pain: phase I.  Anesthesiology 1989; 71: 647 - 52.

128.  Post C, Gordh T, Minor BG, Archer T, Freedman J.  Antinociceptive effects and spinal cord tissue concentrations after intrathecal injection of guanfacine or clonidine into rats.  Anesth Analg 1987; 66: 317 - 24.

129.  Moore A, Collins S, Carroll D, McQuay H.  Paracetamol with and without codeine in acute pain: a quantitative systematic review.  Pain 1997; 70: 193 - 201.

 

General Practice • Anaesthesia •  Pharmacy • Medicine

Home • Journals • Search • Rules for Authors • Submit a Paper • Sponsor us   

priory.com
Home
Anaesthesia
Search
Rules for Authors
Submit a Paper
Sponsor Us

Google Search


Advanced Search

 


 


 

Default text | Increase text size