Efficacy and safety of oral nalbuphine extended release in prurigo nodularis: results of a phase 2 randomized controlled trial with an open-label extension phase.

BACKGROUND: Treatment of prurigo nodularis (PN) is challenging and new treatment options are needed. OBJECTIVE: To evaluate the efficacy and safety of two oral doses of the kappa opioid agonist and mu opioid antagonist nalbuphine extended release (NAL-ER) tablets in a phase 2, multicentre, randomized, double-blind, placebo-controlled trial with an open-label, 50-week extension phase. METHODS: Subjects with moderate-to-severe PN were randomized to NAL-ER 81 mg (NAL-ER81) or 162 mg (NAL-ER162) tablets twice-daily or placebo for 8 weeks of stable dosing following a 2-week titration period. Subjects completing Week 10 with a Worst Itch Numerical Rating Scale (WI-NRS) score ≥5 at the time of rollover (or during the observation period) were eligible for open-label treatment. RESULTS: Of 63 randomized subjects, 62 were treated and comprised the modified intent-to-treat population (MITT), 50 completed 10 weeks of treatment. In the MITT analysis, 8 subjects (44.4%) treated with NAL-ER162 (P = 0.32) and 6 (27.3%) treated with NAL-ER81 (P = 0.78) achieved ≥30% reduction from baseline in 7-day WI-NRS at Week 10 (primary efficacy endpoint) vs. 8 (36.4%) in the placebo group. Itch reduction was significant among 8/12 (66.7%) subjects completing Week 10 treated with NAL-ER162 vs. placebo (8/20, 40.0%; P = 0.03). Additionally, 6 subjects (33.3%) treated with NAL-ER162 and 3 (13.6%) treated with NAL-ER81 achieved ≥50% reduction from baseline in 7-day WI-NRS at Week 10 (coprimary endpoint). Extended open-label treatment was associated with further improvements in itch reduction and favourable changes in PN lesion activity as assessed by Prurigo Activity Score. Adverse events occurred predominantly during dose titration and were of mild-to-moderate severity. The safety profile did not change with extended open-label treatment. CONCLUSION: In adult subjects with PN, oral treatment with NAL-ER 162 mg twice daily provided measurable anti-pruritic efficacy in subjects completing ≥10 weeks of treatment and was well tolerated (ClinicalTrials.gov: NCT02174419).

Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo.

BACKGROUND: Currently available tools to monitor patients with chronic prurigo over time focus on pruritus and quality of life parameters, while no instrument objectively assessing the pruriginous lesions is yet available. OBJECTIVE: The objective of this study was to develop a physician-assessed Prurigo Activity Score (PAS), a new tool to monitor the distribution and activity of chronic prurigo lesions and to evaluate its reliability and validity. METHODS: The 7-item PAS questionnaire as well as validated pruritus intensity scales (VAS, NRS) and a skin-related quality of life score (DLQI) were completed for 264 patients (172 females, age 61 years) at least twice over a period of 2 years. In addition, a 60-min test-retest reliability test was performed by four experts for a random sample of 12 patients. RESULTS: The PAS showed good test-retest reliability (Cohens κ > 0.61; Cronbach-alpha > 0.76), ordinal or metric items showed high inter-rater reliability (Kendalls > 0.61) and items recording the number of lesions correlated significantly to each other (P < 0.001). The highest correlation to external constructs was achieved with DLQI. The feasibility test conducted by four raters indicated the suitability of PAS for tracking chronic prurigo in the clinical setting. DISCUSSION: The PAS is a useful tool to objectively monitor pruriginous lesions in chronic prurigo patients over time. The sensitivity of change in the PAS score should be analysed in future studies.

Lack of association between skin tags and colon polyps in a primary care setting.

Cutaneous skin tags (acrochordons) have recently been proposed as markers for adenomatous polyps of the colon among symptomatic patients referred for colonoscopy. To ascertain the utility of skin tags as a predictor of colonic polyps in a primary care setting, 492 patients, with a mean age of 58 +/- 13.3 years (241 with signs or symptoms and 251 for screening), were evaluated for the presence of skin tags and then examined using a 60-cm fiberoptic sigmoidoscope by an examiner "blinded" to the skin findings. Among patients with skin tags, 23 (10.2%) of 226 had polyps, whereas among patients without skin tags, 20 (7.5%) of 266 had polyps. The predictive value of the presence of a skin tag was 10.2%. Contrary to studies done in more selected populations with a higher prevalence of adenomatous polyps, the results using a 60-cm flexible sigmoidoscope in a primary care population suggest that cutaneous skin tags are not a marker for adenomatous polyps of the colon.

Ultrastructural and x-ray microanalytical observations of minocycline-related hyperpigmentation of the skin.

In order to elucidate the nature and distribution of the pigment responsible for the circumscribed blue-black cutaneous hyperpigmentation occurring after administration of minocycline hydrochloride, transmission electron microscopy and energy-dispersive electron x-ray microanalysis were performed on lesional skin. Ultrastructural observations demonstrated electron-dense iron-containing particles either incorporated into a variety of siderosomes, within dermal histiocytes, free within the cytoplasm, or, rarely, scattered among dermal collagen fibers. Electron x-ray microanalysis confirmed iron content present within these particles. Although siderosomal inclusions contained occasional melanosome complexes, the degree of deposition of electron-dense iron-containing particles in dermal histiocytes seemed to be primarily responsible for the blue-black discoloration of the skin. The present study is an investigation of the structure and composition of the pigment responsible for minocycline-related cutaneous hyperpigmentation.

The Koebner (isomorphic) response in psoriasis. Associations with early age at onset and multiple previous therapies.

Among 1,253 patients with psoriasis who were enrolled in a study of photochemotherapy, 33% had a history of a Koebner response (KR) at the site of physical trauma. The early onset of psoriasis and previous treatment with multiple types of therapy were each independently associated with the KR. Among patients with both onset before age 15 years and previous treatment with four or more types of therapy, 75% reported the KR, compared with only 5% of patients with onset after age 30 years and no previous therapy. At the time of enrollment in the photochemotherapy study, the history of the KR was not associated with worsening, the duration of psoriasis, or the extent of skin surface involved. Patients with the KR may manifest their disease earlier in life or may be more prone to flare after any type of treatment.

Inflammatory linear verrucous epidermal nevus. Epidermal protein analysis in four patients.

Inflammatory linear verrucous epidermal nevus (ILVEN) may be difficult to differentiate clinically from psoriasis. We report four cases of ILVEN that confirm the observation that the analysis of epidermal proteins by sodium lauryl sulfate-polyacrylamide gel electrophoresis (SLS-PAGE) discloses a pattern different from that seen in psoriasis. We have also found, however, that the SLS-PAGE epidermal protein pattern is not identical in each case of ILVEN.

Antihistamine update.

Antihistamines are a diverse group of drugs, each possessing the ability to inhibit various actions of histamine. Because they act principally through competitive inhibition of the histamine receptor, they are helpful as a means of preventing rather than reversing these actions. As a result of a resurgence of interest in antihistamine therapy during the past decade, a new class of H1 blockers, clinically devoid of sedative and anticholinergic effects, has evolved. Thus, the choice of antihistamine can now be based on the side effects profile as well as the clinical profile. As we continue to develop a better understanding of these newer agents, we will be able to select more rationally the antihistaminic agent most appropriate to the specific disorder. Used judiciously, the antihistamines available today have a broad application of therapeutic uses, with few significant side effects.

Nonrashes. 5. Atmoknesis: pruritus provoked by contact with air.

Atmoknesis, itching provoked by open exposure of the skin to air after undressing, is a common and distressing symptom. It occurs in many patients with psoriasis and atopic dermatitis, and in elderly patients with aquagenic pruritus. It also occurs in some patients with underlying systemic causes of generalized pruritus, such as hepatobiliary disease. It does not seem to be an important feature of certain other pruritic skin diseases such as dermatitis herpetiformis and bullous pemphigoid.

Nonrashes. 4. Audible signs of cutaneous disease.

There is more than one reason why dermatologists should listen to their patients. Audible signs of cutaneous disease range from the classic, early childhood hoarseness of lipoid proteinosis to a characteristic hoarseness due to syphilitic papules on the epiglottis and arytenoepiglottic folds.

Recurrence of lichen simplex chronicus after surgical excision.

The case of a woman who developed recurrent lichen simplex chronicus almost two years after the original lesion was surgically excised is reported.

Nonrashes. Part I: The Koebner nonreaction.

"Nonrashes" range from pruritus that may signal an underlying systemic illness to delusional parasitosis associated with severe psychological disturbance. We report another kind of nonrash, the Koebner nonreaction or isomorphic nonresponse, that was manifested by the absence of a drug rash at the site of recently administered x-irradiation. We also present a compilation of a number of other nonrashes, such as the mitempfindungen (referred itch) and the prodrome of herpes zoster. The recognition of certain types of nonrashes may be lifesaving.

Nonrashes. 6. Telepathic pruritus.

We report the case of a paranoid schizophrenic man who suffered from the delusion that two other men used mental telepathy to make him itch over a period of thirteen years. To our knowledge, this is the first report of "telepathic pruritus."

Incarceration for excoriation.

A thirty-six-year-old man experienced acute, severe, generalized pruritus. His scratching was erroneously interpreted as lewd and indecent behavior. He was arrested. Results of the history and physical examination led to the diagnosis of fiberglass dermatitis, which prompted a dismissal of the charges. Although many societies have looked askance at persons with certain skin diseases (such as leprosy) and at scratching in public since at least biblical times, we are not aware of any prior reports of incarceration for excoriation.

Phototherapy and photochemotherapy in dermatologic diseases.

Phototherapy and photochemotherapy have been shown to be effective treatments in a number of cutaneous disorders, but they are not without risk. PUVA has revolutionized the treatment of psoriasis and stimulated major improvements in the administration of UVB therapy. Successful treatment depends on careful patient selection and evaluation. Accurate dosimetry and close supervision are necessary to avoid complications. Regular and careful follow-up, both during and after therapy, can help to identify and treat long-term side effects such as non-melanoma skin cancers. In order to achieve the necessary balance between benefits and risks with these valuable forms of therapy, patients should be referred to dermatologists with special training.

Review of pruritus therapy.

Treatment of pruritus is based on determining the etiology of the itch. The evaluation should include a detailed history, complete physical examination, and appropriate laboratory tests. There are many therapies available, and treatment should be tailored to the individual patient.