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Clonidine-creme tegen chronische neuropathishe pijn

Clonidine is een bloeddrukverlagend middel en de werking daarvan is ook onderzocht in een creme bij neuropathische en neuralgische pijnklachten.

Ons instituut werkt momenteel (anno 2012) aan een clonidine-creme in INP basis, om alleen of samen met de ketamine-creme de problematische pijnen bij neuropathie, en bij CRPS (Sudeck) te verminderen.  

Deze bloeddrukverlager, een α2-adrenerge agonist, is onderzocht in cremevorm in een open studie met 10 neuropathische en 7 neuralgische patienten met pijn rond en in de mond. De creme met 0,2 mg/g (0,2%) clonidine werd 4 maal per dag op de pijnplek gesmeerd. De helft van de patienten met neuropathie had duidelijk een pijnvermindering (vermindering in het branderige gevoel) en gemiddeld voor de hele groep een vermindering van 36%. In de groep van patienten met neuralgie had 57% een duidelijke vermindering van de pijnklachten.[1]

In een kleine dubbelblinde studie bleek dat clonidine bij een aantal patienten duidelijk effect had. Dit werd duidelijk omdat wanneer de patienten geen clonidinepleister kregen,  de pijnweer  heviger werd. De hoeveelheid clonidine via de pleisters was 0,3 mg per dag.[2]

Een andere grote dubbelblinde studie onderzocht clonidine 0,1% creme bij diabetespatienten met neuropathische pijn.[3] Eerst werd capsaicine creme (hete peper creme) op de pijnplekken gesmeerd om te evalueren of de patienten meer pijn ervoeren. Daarna werden de patienten verdeeld over twee groepen: clonidine 0,1% en placebo. Vooral de patienten die met meer pijn reageerden op capsaicine creme, hadden duidelijk  meer pijnverlichting dan de placebogroep.

Gel: ketamine, clonidine, gabapentine bij neuropathie 

Een gel met ketamine 5%, clonidine 0.5% en gabapentine 6% werd toegepast bij een patient met neuropathische pijn na chemotherapie met Bortezomib vanwege monoclonale gammopathie. Hij had een pijnscore tussen de 8 en 10.

Na het smeren had hij direct effect en daalden zijn pijnscores naar 5. Door de ketamine op te hogen naar 10% werd de pijn verder verminderd naar 3.

Deze creme werd gegeven omdat gabapentine en lidocainepleisters nagenoeg geen effect hadden en de patient behoorlijke bijwerkingen had van de morfine. Alle orale medicatie werd afgebouwd en de patient ervoer geen bijwerkingen van de creme.[4]

Clonidine voor flushing

In de VS is clonidine cream ook als magistrale creme verkrijgbaar: 

Clonidine cream is now available for topical use; however, it is only available through Communitydrug.com. You can order it in prescription form (0.5% – 2.0%) in a non-alcoholic base. You and your physician need to understand though that it is still in the experimental stages for treating facial pain/burning symptoms (as well as its potential effect on facial erythema). I have a few positive reports back (and one negative report) from people on the facial flushing/blushing board who have been testing this topical medicine. The physician that writes anyone out a prescription for this topical should follow the patient closely. 

Dierstudies met clonidine creme

Ook in ratmodellen voor neuropathische pijn had clonidine creme effect op de pijn.[5] Omdat op de pijnvezels ook α2-adrenerge receptoren zitten, heeft clonidine ook effect wanneer de clonidine via de huid wordt aangeboden. Ketamine, een NDMA antagonist, heeft geen invloed op het effect van clonidine. Clonidine via de huid had geen bijwerkingen in dit diermodel.[6]

Clonidine creme, patent literatuur

In het volgende oktrooi, United States Patent 6147102 de rationale van clonidine bij pijn: 

Clonidine, in particular, is a potent α2 -adrenergic partial agonist used primarily for the treatment of hypertension (Jarrott et al., "Clonidine: Understanding its disposition, sites, and mechanism of action", Clin. Exp. Pharm. Physiol., 14, 471-479 (1987)).

This drug stimulates α2 -adrenoceptors in the vasomotor centers, causing a reduction of sympathetic outflow from the central nervous system.

Both cardiac output and peripheral resistance are reduced resulting in a decrease in blood pressure. Higher concentrations cause a vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle. However, the significant advantages of the drug are counter balanced by certain troublesome side effects including dryness of the mouth and a discouraging dizziness.

Therefore, the blood concentration of clonidine must be controlled within a narrow therapeutic window.

Clonidine and related α2 -adrenergic agonists have been reported to modify nociception in animal models. See Yaksh, T. L., "Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing", Pharmacol. Biochem. Behav., 22, 845-858 (1985); and Nakamura et al., "Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances", Eur. J. Pharmacol., 146, 223-228 (1988).

In clinical studies, single doses of epidural clonidine have been reported to relieve post-operative pain (Mendez et al., "Epidural clonidine analgesia after cesarean section", Anesthesiology, 73, 848-852 (1990)), cancer pain (Eisenach et al., "Epidural clonidine analgesia for intractable cancer pain:phase I", Anesthesiology, 71, 647-552 (1989)), and pain due to arachnoiditis (Glynn et al., "A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain", Pain, 34, 123-128 (1988)).

In a controlled trial of single oral doses of 0.2 milligrams (mg) clonidine in 40 patients with postherpetic neuralgia, observed pain relief was greater than that produced by doses of placebo or 120 mg codeine, but the modest analgesia was accompanied by troublesome levels of sedation and dizziness at the time of peak clonidine levels. (Max et al., "Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo", Clin. Pharmacol. Ther., 43, 363-371 (1988)).

Some attempts have been made to relieve pain, allodynia and hyperalgesia employing transdermal patches containing clonidine, but the effects achieved were restricted to the skin underlying the patch. Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold or an increase in pain to suprathreshold stimuli or both is observed. The decrease in pain threshold to mechanical or thermal stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.

For example, Davis et al., in "Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain," Pain, 47, 309-318 (1991) reported that delivery of clonidine by transdermal patch relieved sympathetically maintained hyperalgesia in the skin adjacent to the patch Likewise, Campbell in U.S. Pat. No. 5,447,947 describes hyperalgesia relief with transdermal patches delivering a systemic dose of 0.2 mg and 0.3 mg of clonidine/day (i.e., 30 micrograms/square centimeter patch/day), but the zone of relief was generally limited to the skin area at or adjacent the patch site along with some skin irritation surrounding the patch site and side effects were noted.

In a placebo-controlled cross-over pain trial in patients with painful diabetic neuropathy utilizing clonidine transdermal patches no statistically significant differences between treatments were observed by Zeigler et al., "Transdermal clonidine versus placebo in painful diabetic neuropathy", Pain, 48, 403-408 (1992). In a follow-up placebo controlled pain study in similar patients with painful diabetic neuropathy, transdermal clonidine patches were evaluated using a two-stage enriched enrollment design by Byas-Smith et al., "Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage enriched enrollment’ design", Pain, 60, 267-274 (1995).

Only twelve of forty-one patients (29%) who completed the initial course of treatment were considered clonidine responders. These twelve clonidine responders were then rechallenged in a second placebo controlled study which used the highest dosage available with the transdermal patch system.

The pain reduction relative to placebo tended to be modest although statistically significant (p<0.015). Based on the foregoing attempts it would appear that relatively higher concentrations of clonidine are needed at the painful site. Unfortunately, with the dosage forms utilized, higher doses cannot be given without accompanying undesirable systemic side effects.

While clonidine is a desirable potent analgesic drug, it has a narrow therapeutic index. A desirable treatment for sympathetically maintained peripheral neuropathic pain syndromes, therefore, would be a topical composition of clonidine that could be spread over the entire painful area to deliver targeted high concentrations to the painful site yet affording minimum systemic concentrations.  

Verder lezen

Byas-Smith et al., "Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two-stage `enriched enrollment` design," Pain, 60, 267-274 (1995) (abstract).

Davis et al., "Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain," Pain, 47, 309-317 (1991) (abstract). Eisenach et al., "Epidural clonidine analgesia for intractable cancer pain:phase I," Anesthesiology, 71, 647-552 (1989) (abstract).

Epstein et al., "Topical clonidine for orofacial pain: a pilot study," J. Orofac. Pain, 11, 346-352 (1997) (abstract). Glynn et al., "A double-blind comparison between epidural morphine and epidural clonidine in patients with chronic non-cancer pain," Pain, 34, 123-128 (1988) (abstract).

Langley et al., "Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy," Drugs, 35, 123-142 (1988) (abstract).

Max et al., "Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen and placebo," Clin. Pharmacol. Ther., 43, 363-371 (1988) (abstract).

Mendez et al., "Epidural clonidine analgesia after cesarean section," Anesthesiology, 73, 848-852 (1990) (abstract).

Nakamura et al., "Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances", Eur. J. Pharmacol., 146, 223-228 (1988) (abstract).

Yaksh, T.L., "Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing", Pharmacol. Biochem. Behav., 22, 845-858 (1985) (abstract).

Zeigler et al., "Transdermal clonidine versus placebo in painful diabetic neuropathy," Pain, 48, 403-408 (1992) (abstract).  

Auteurs: Prof.dr. Jan M. Keppel Hesselink, MD, PhD en Drs David J. Kopsky, MD, versie september 2009, revisie maart 2012, JMKH; revisie juni 2012, JMKH, revisie DJK augustus 2012 

Referentie

[1] Epstein JB, Grushka M, Le N. | Topical clonidine for orofacial pain: a pilot study. | J Orofac Pain. | 1997 Fall;11(4):346-52.

[2] Zeigler D, Lynch SA, Muir J, Benjamin J, Max MB. | Transdermal clonidine versus placebo in painful diabetic neuropathy. | Pain. | 1992 Mar;48(3):403-8.

[3] Campbell CM, Kipnes MS, Stouch BC, Brady KL, Kelly M, Schmidt WK, Petersen KL, Rowbotham MC, Campbell JN. | Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. | Pain. | 2012 Sep;153(9):1815-23. Epub 2012 Jun 8.

[4] Prommer EE. | Topical analgesic combinations for bortezomib neuropathy. | J Pain Symptom Manage. | 2009 Mar;37(3):e3-5. Epub 2009 Jan 25.

[5] Li C, Sekiyama H, Hayashida M, Takeda K, Sumida T, Sawamura S, Yamada Y, Arita H, Hanaoka K. | Effects of topical application of clonidine cream on pain behaviors and spinal Fos protein expression in rat models of neuropathic pain, postoperative pain, and inflammatory pain. | Anesthesiology. | 2007 Sep;107(3):486-94.

[6] Dogrul A, Uzbay IT. | Topical clonidine antinociception. | Pain. | 2004 Oct;111(3):385-91.

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