Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 16–18
doi: 10.1111/jcpt.12005
Treatment of prurigo nodularis with pregabalin M. Mazza* MD PhD, G. Guerriero MD, G. Marano* MD, L. Janiri* MD, P. Bria* MD and S. Mazza MD* *Department of Neurosciences, Universita` Cattolica del Sacro Cuore di Roma, Roma, Italy and Department of Dermatology, Universita` Cattolica del Sacro Cuore di Roma, Roma, Italy
Received 20 November 2011, Accepted 9 August 2012
Keywords: itching, nodules, pregabalin, prurigo
the stress response with strong pruritogenic potential need to be further explored systematically in order to develop more effective therapeutic combination strategies for PN and other chronic stress-vulnerable inflammatory skin diseases.6 PN is often refractory to classical treatment with topical corticosteroids and antihistamines. In a number of case series and case reports, systemic l-opioid receptor antagonists, such as naloxone, nalmefene and naltrexone have been used to treat PN and various forms of chronic pruritus (cholestatic pruritus, chronic urticaria, atopic dermatitis). However, most of the evidence for efficacy remains anecdotal.7 Phototherapy, erythromycin, retinoids, cyclosporine, azathiopurine and other psychopharmacological agents (pimozide and selective serotonin reuptake inhibitor antidepressants) have been tried with some success.8–11 Some authors have claimed efficacy for thalidomide, a drug that has to be carefully monitored because of its neurotoxicity and therefore is often discontinued by patients.12 Dereli et al.13 have described a patient with PN who responded well to the treatment with gabapentin and more recently Gencoglan et al.14 described five cases of lichen simplex chronicus and four cases of PN who responded well to gabapentin. Pregabalin shares with gabapentin a similar mechanism of action, inhibiting calcium influx and subsequent release of excitatory neurotransmitters.15,16 However, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect. Orally administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within 1 h. Absorption is linear, with plasma concentrations increasing proportionately with increasing dose and absolute bioavailability of pregabalin remains at > or =90% irrespective of the dosage. It neither bind to plasma proteins nor is metabolized or inhibits hepatic enzymes that are responsible for the metabolism of other drugs. It is excreted renally, with elimination half-lives of approximately 6 h.15 We aimed to investigate the efficacy of pregabalin in patients with PN.
SUMMARY What is known and objective: Prurigo nodularis (PN) is a chronic skin condition that is difficult to treat. Pregabalin is one of the possible treatments for PN but its safety and efficacy are not well defined. We aimed to assess the efficacy of pregabalin in patients with PN. Methods: Thirty patients (10 men, 20 women; mean age 51.6 ± 9.39 years) were treated with pregabalin (75 mg/day) for 3 months. Efficacy was classified as (i) successful (disappearance of the pruritus and reduction of nodules); (ii) slight improvement/reduction of the nodules, that is, number and/or flattening, no disappearance of itching; or (iii) unsuccessful. Results: Twenty-three patients (76%) responded successfully after 3 months of treatment. There was a statistically significant difference between visual analogue scale scores before and after 1 month treatment period (8Æ15 ± 2Æ04 and 1Æ5 ± 1Æ12, respectively; P < 0Æ0001). Pregabalin was generally well tolerated with only six (20%) patients reporting side effects. No patient showed any renal insufficiency. What is new and conclusion: In our study, pregabalin was effective for the treatment of PN. However, given the open and non-controlled study design used, a properly powered randomized controlled validation study is called for. WHAT IS KNOWN AND OBJECTIVE Prurigo nodularis (PN) is a benign dermatitis of unknown aetiology characterized by firm, hyperkeratotic pruritic nodules most commonly localized symmetrically on the bilateral extensor lower extremities.1 It is a difficult-to-treat chronic skin condition. Interruption of the itch-scratch cycle is difficult and longterm prognosis remains guarded. Some studies show that symptoms of anxiety and depression are often present in patients with PN, along with some specific traits of personality.2 PN in fact has also been classified in the category of ‘psychocutaneous disorders’;3 a recognition of the contribution of psychogenic factors in this condition.4 Nerve growth factor has been implicated in the pathogenesis of PN. Calcitonin gene-related peptide and substance P immunoreactive nerves are markedly increased in PN when compared with normal skin. These neuropeptides may mediate the cutaneous neurogenic inflammation and pruritus in PN.5 For this reason, some authors argue that key candidate molecules of
METHODS We included all patients referred to A. Gemelli Hospital in Rome between September 2007 and November 2009 for the treatment of PN. The study included patients diagnosed with PN who were willing to discontinue their currently prescribed treatment. Patients who had been previously treated with pregabalin but failed to improve or did not tolerate this drug were excluded, as were pregnant or lactating women. All patients underwent blood analysis as suggested in the data sheet of pregabalin. No concomitant therapy was allowed or applied. As rescue medication, antihistamines were recommended with the
Correspondence: M. Mazza, Department of Neurosciences, Universita` Cattolica del Sacro Cuore di Roma, Via Ugo De Carolis, 48 00136 Roma, Italy. Tel.: +39 06 35348285; fax: +39 06 35501909; e-mail:
[email protected];
[email protected]
ª 2012 Blackwell Publishing Ltd
16
M. Mazza et al.
Pregabalin and prurigo
Treatment with pregabalin had to be discontinued in two patients (6%) because of side effects (sedation and headache). Pregabalin was generally well tolerated with only six (20%) patients reporting side effects. No patient showed any renal insufficiency by the treatment with pregabalin. There was a statistically significant difference between VAS values before and after the 3 months treatment period (8Æ15 ± 2Æ04 and 1Æ5 ± 1Æ12, respectively; P < 0Æ0001). Pathways for itch and pain are similar, both involving transmission by specialized C-fibres in the dorsal horns of medulla spinalis and reaching the thalamus and the somatosensory cortex via the lateral spinothalamic tract.18 The close relationship between these pathways suggests that pregabalin may inhibit the sensation of itching. In particular, the results of experiments on mice suggest that pregabalin may exert an antipruritic effect through a2 d-1 subunit binding of voltage-gated Ca2(+) channels and the up-regulation of the a2 d-1 subunit in dorsal root ganglion.19 There is evidence of successful use of pregabalin in neuropathic itch 20 and in uraemic pruritus in haemodialysis patients.17 In this study, the dosage of pregabalin can be considered low with 75 mg/day. In fact, the usual dosage is 150–300 mg per day for the treatment of seizures, neuropathic pain, fibromyalgia and generalized anxiety disorder. Usually physicians start the patient on a low dose of pregabalin and increase it gradually if the patient reports little or no clinical improvement.15 In this
indication to immediately contact clinicians if used but no patient used them during the study. Efficacy was classified as (i) successful (disappearance of the pruritus and reduction of nodules); (ii) slight improvement/reduction of the nodules, that is, number and/or flattening, no disappearance of itching; or (iii) unsuccessful.12 Any side effects arising during treatment were recorded. The effectiveness of pregabalin was also evaluated using a visual analogue scale (VAS) before and after 3 months of treatment. VAS consisted of a 10-cm horizontal line scored from 0 (no itch) to 10 (worst imaginable itch).17 All patients provided written informed consent before beginning any study activities. The protocol was approved by the local Ethics Review Board. RESULTS Thirty patients (10 men, 20 women; mean age 51.6 ± 9.39 years) were treated with pregabalin (75 mg/day, at the dosage of 25 mg t.i.d) (Table 1). None of them had any underlying disease responsible for the PN, and all had responded poorly to previous treatments. Twenty-three patients (76%) showed complete response after 3 months of treatment, with 21 continuing on maintenance treatment of 50 mg/day at the time of last followup (24 months). Six patients (20%) showed slight improvement, and the treatment was judged to be unsuccessful in only one patient.
Table 1. Patients characteristics and details of pregabalin treatment (75 mg/day) Patient
Age
Sex
Disease duration (years)
Clinical response (after 3 months)
Side effects
Evolution (24 months)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
52 57 50 39 61 62 41 47 48 50 53 42 65 66 37 44 37 45 54 54 60 66 63 55 49 48 61 65 37 40
F F F M M M M M M M F F M F F F F F F F F F F F M F F F F M
3 12 10 4 6 6 8 2 3 2 11 12 18 13 5 5 8 10 7 10 4 4 2 3 7 10 10 15 2 4
Slight improvement Successful Successful Successful Successful Successful Successful Successful Successful Successful Successful Successful Slight improvement Successful Successful Slight improvement Unsuccessful Successful Successful Successful Successful Successful Successful Slight improvement Slight improvement Slight improvement Successful Successful Successful Successful
Sedation No No No No No Dizziness No No No No No Sedation No No No Headache No No No No No No No No No No Sedation No No
Stopped because of SE MD = 50 mg/day Lesion free Lesion free MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day Lesion free Lesion free MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day Lesion free Lesion free MD = 50 mg/day Stopped because of SE MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day Lesion free MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day MD = 50 mg/day
F, female; M, male; SE, side effect; MD, maintenance dose.
ª 2012 Blackwell Publishing Ltd
Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 16–18 17
M. Mazza et al.
Pregabalin and prurigo
study, patients were seen at baseline and every 2 weeks for dose adjustments. Clinical investigators responsible for dosage adjustments and adverse reactions monitoring decided to leave the dosage at 75 mg/day because of good tolerability and rapid response seen.
a properly powered randomized controlled validation study is called for. This study needs to be interpreted with caution because of some limitations. First, not using a control group is an important weakness that tempers the relevance of the results. Second, the small sample size does not allow firm conclusions to be drawn. Despite these points, results from this study seem to support the safety and the potential efficacy of pregabalin for the treatment of PN. This work should be replicated comparing pregabalin with placebo and other medications in a larger sample of patients.
WHAT IS NEW AND CONCLUSION In our study, pregabalin was effective for the treatment of PN. However, given the open and non-controlled study design used,
REFERENCES 1. Vaidya DC, Schwartz RA. Prurigo nodularis: a benign dermatosis derived from a persistent pruritus. Acta Dermatovenerol Croat, 2008;16:38–44. 2. Dazzi C, Erma D, Piccinno R, Veraldi S, Caccialanza M. Psychological factors involved in prurigo nodularis: a pilot study. J Dermatolog Treat, 2011;22:211–214. 3. Elpem DJ. Toward a better understanding of ‘‘psychocutaneous disorders’’. Int J Dermatol, 2009;48:1395–1396. 4. Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther, 2008;21:42–46. 5. Lee MR, Shumack S. Prurigo nodularis: a review. Australas J Dermatol, 2005;46:211–218. 6. Arck P, Paus R. From the brain-skin connection: the neuroendocrine-immune misalliance of stress and itch. NeuroImmuno Modulation, 2006;6:347–356. 7. Phan NQ, Bernhard JD, Luger TA, Stander S. Antipruritic treatment with systemic lopioid receptor antagonists: a review. J Am Acad Dermatol, 2010;63:680–688. 8. Slepmann D, Luger TA, Stander S. Antipruritic effect of cyclosporine microemulsion in prurigo nodularis: results of a case
9.
10.
11. 12.
13.
14.
15.
series. J Dtsch Dermatol Ges, 2008;6:941– 946. Horiuchi Y, Bae S, Katayama I. Uncontrollable prurigo nodularis effectively treated by roxithromycin and tranilast. J Drugs Dermatol, 2006;5:363–365. Hammes S, Hermann J, Roos S, Ockenfels HM. UVB 308-nm excimer light and bath PUVA: combination therapy is very effective in the treatment of prurigo nodularis. J Eur Acad Dermatol Venereol, 2011;25:799– 803. Wallengren J. Prurigo: diagnosis and management. Am J Clin Dermatol, 2004;5:85–95. Taefehnorooz H, Truchetet F, Barbaud A, Schmutz J, Bursztejn A. Efficacy of thalidomide in the treatment of prurigo nodularis. Acta Derm Venereol, 2011;91:344–345. Dereli T, Karaca N, Inanir I, Ozturk G. Gabapentin for the treatment of recalcitrant chronic prurigo nodularis. Eur J Dermatol, 2008;18:85–86. Gencoglan G, Inanir I, Gunduz K. Therapeutic hotline: treatment of prurigo nodularis and lichen simplex chronicus with gabapentin. Dermatol Ther, 2010;23:194– 198. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A comparison
ª 2012 Blackwell Publishing Ltd
16.
17.
18.
19.
20.
of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet, 2010;49:661–669. Quintero JE, Dooley DJ, Pomerleau F, Huettl P, Gerhardt GA. Amperometric measurement of glutamate release modulation by gabapentin and pregabalin in rat neocortical slices: role of voltage-sensitive Ca2+ a2d-1 subunit. J Pharmacol Exp Ther, 2011;338:240–245. Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. J Ren Care, 2010;36:180–185. Paus R, Schmelz M, Biro T, Steinhoff M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest, 2006;116:117. Tsukumo Y, Matsumoto Y, Miura H, Yano H, Manabe H. Gabapentin and pregabalin inhibit the itch-associated response induced by the repeated application of oxazolone in mice. J Pharmacol Sci, 2011;115:27–35. Thielen AM, Vokatch N, Borradori L. Chronic hemicorporal prurigo related to a post-traumatic Brown-Sequard syndrome. Dermatology, 2008;217:45–47.
Journal of Clinical Pharmacy and Therapeutics, 2013, 38, 16–18 18
