Skin ulcerations caused by xylazine: A lesser-known entity

An increasing number of media reports are discussing severe skin ulcerations associated with the use of xylazine in persons who inject drugs (PWID). Xylazine, a nonopioid, lipophilic sedative with central alpha-2 agonist activity, is US Food and Drug Administration–approved for pain management in veterinary medicine owing to its sedative, analgesic, and muscle relaxant effects. Xylazine, also called tranq, tranq dope, Philly dope, sleep-cut, zombie drug, horse anesthetic, and rhinoceros tranquilizer, has increasingly been reported to be present in drug cocktails injected by PWID (most commonly with fentanyl) from Pennsylvania.1Bettigole C. Best A. Teixeira D. Xylazine (tranq) exposure among people who use substances in Philadelphia. Health update, substance use prevention and harm reduction. Department of Public Health City of Philadelphia.https://hip.phila.gov/document/3154/PDPH-HAN_Update_13_Xylazine_12.08.2022.pdf/Date accessed: March 22, 2023Google Scholar Because of serious side effects stemming from xylazine contamination of common illicit drugs,2Friedman J. Montero F. Bourgois P. et al.Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis.Drug Alcohol Depend. 2022; 233109380https://doi.org/10.1016/j.drugalcdep.2022.109380Crossref PubMed Scopus (18) Google Scholar a press release was issued by US Food and Drug Administration dated November 8, 2022, advising physicians to keep xylazine adulteration as an important possibility in the setting of nonresponse or partial-response to naloxone in PWID with skin findings of severe, necrotic ulcerations.2Friedman J. Montero F. Bourgois P. et al.Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis.Drug Alcohol Depend. 2022; 233109380https://doi.org/10.1016/j.drugalcdep.2022.109380Crossref PubMed Scopus (18) Google Scholar,3FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs. U.S. Food and Drug Administration.https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugsDate accessed: March 22, 2023Google Scholar Therefore, an awareness regarding the occurrence, possible pathophysiology, and differential diagnoses of xylazine-induced cutaneous ulcerations could help when PWID present with skin ulcers. The chemical structure of xylazine resembles levamisole, another drug known to induce severe skin ulcerations resembling granulomatosis with polyangiitis when adulterated with cocaine.3FDA alerts health care professionals of risks to patients exposed to xylazine in illicit drugs. U.S. Food and Drug Administration.https://www.fda.gov/drugs/drug-safety-and-availability/fda-alerts-health-care-professionals-risks-patients-exposed-xylazine-illicit-drugsDate accessed: March 22, 2023Google Scholar Xylazine-induced skin ulcers are caused by chronic and repetitive usage of the drug and can occur on sites other than the site of injection, or even when the drug is snorted or inhaled. The proposed causes include a predominant peripheral alpha 2 and some alpha 1 adrenergic agonist activity,1Bettigole C. Best A. Teixeira D. Xylazine (tranq) exposure among people who use substances in Philadelphia. Health update, substance use prevention and harm reduction. Department of Public Health City of Philadelphia.https://hip.phila.gov/document/3154/PDPH-HAN_Update_13_Xylazine_12.08.2022.pdf/Date accessed: March 22, 2023Google Scholar which cause vasoconstriction of cutaneous arterioles via Gi (via reduction in cyclic adenosine monophosphate) and Gq (calcium-calmodulin mediated) subunits of G-protein coupled alpha adrenergic receptors, respectively, resulting in tissue ischemia. Additionally, alpha 2 adrenergic agents are associated with local analgesia, which, coupled with ischemia and repeated trauma of injections, leads to extensive ulceration. Further research is needed to rule out if it triggers an immune-mediated vasculopathy. In a report from Puerto Rico, it was observed that xylazine users had a significantly higher prevalence of skin ulcers (38.5% vs 6.8%) and poorer health when compared with PWIDs who did not use xylazine.4Reyes J.C. Negrón J.L. Colón H.M. et al.The emerging of xylazine as a new drug of abuse and its health consequences among drug users in Puerto Rico.J Urban Health. 2012; 89: 519-526https://doi.org/10.1007/s11524-011-9662-6Crossref PubMed Scopus (47) Google Scholar Important clinical differentials in xylazine-induced cutaneous ulcerations in PWID include levamisole-, cocaine-, and pentazocine-induced skin ulcers (Table I)5Malayala S.V. Papudesi B.N. Bobb R. Wimbush A. Xylazine-induced skin ulcers in a person who injects drugs in Philadelphia, Pennsylvania, USA.Cureus. 2022; 14e28160https://doi.org/10.7759/cureus.28160Crossref Google Scholar; necrotizing fasciitis; pyoderma gangrenosum and vasculitic ulcers; acute limb ischemia; and embolia cutis medicamentosa. It is important to remember that more than one of these causes can contribute to skin ulcerations in these patients owing to polysubstance abuse; coexistent hepatitis B, C, and HIV infections; and physical factors, like the type and formulations of the drugs and methods of injection.Table IClinical differentials in skin ulcers in persons who inject drugsClinical settingMorphologyInvestigationsComplicationsManagementXylazine -induced skin ulcerationCommon adulterants in opioids, especially fentanyl, to increase the onset and duration of euphoria achieved by using fentanyl. Xylazine toxicity should be suspected in a patient who is not responding to naloxone and has severe skin ulcers. More common with intradermal rather than intravenous administration of the drug.Foul smelling, progressive, large painful ulcerations, most commonly on the lower portion of the legs, commonly extending up to the bone. Coexistent cellulitis, necrotizing fasciitis, myositis, and osteomyelitis are common. Can resemble dermatitis artefacta.Xylazine has a very short half-life of 25-30 minutes, and therefore, is difficult to detect by routine toxicological analysis unless consumed recently.Ultrasound of the ulcerated area and cultures from the skin and blood should be sent to rule out secondary infections, which are usually polymicrobial and unusual pathogens. X-rays and MRI can be performed to rule out osteomyelitis.Can result in respiratory and central nervous system depression not reversed by naloxone. Concomitant bradycardia, hypotension, and cardiac arrhythmia should lead to suspicion of xylazine adulteration. Withdrawal from xylazine cannot be managed using methadone, naltrexone, or buprenorphine. Skin ulcers can get infected and lead to sepsis.Stopping the abuse. Wound care, debridement, drainage, skin grafts, topical epidermal growth factors, and amputation.Levamisole - induced skin ulceration (LINES, levamisole adulterated cocaine vasculopathy)Levamisole is added to cocaine to enhance its effects and to add bulk to these expensive drugs. The ulcerations are thought to be a result of a combination of levamisole-induced vasculitic changes coupled with probably cocaine-induced vasoconstriction. Lesions can occur away from the head and neck, and on the areas distinctly away from sites where cocaine is snorted.Levamisole -induced painful and necrotic skin ulcerations are surmounted on inflammatory retiform purpura. These are more common on the face (nose, cheeks, and ears) and lower portion of the limbs, resembling granulomatosis with polyangiitis, and are usually associated with neutropenia and thrombocytopenia. These lesions can also mimic cryoglobulinemic vasculitis.Levamisole levels can be undetectable in urine toxicological analysis, especially if the intake was >12 hours prior. Inflammatory vasculitis and thrombotic vasculopathy are seen on skin biopsy samples.High-titer ANCA and antiphospholipid antibodies are usually present. p-ANCA (directed to HNE and PR-3) are significantly more common than c-ANCA.Autoamputation of the nose and ears where abuse does not stop. Secondary infection is common because of associated agranulocytosis and can result in associated sepsis, purpura fulminans, and infective endocarditis.Stopping cocaine abuse usually helps. Wound care, debridement, skin grafts, and amputation. The role of prednisolone is doubtful and should be used with caution in people having neutropenia.CIMDLCocaine abuse can occur in isolation or in conjunction with levamisole abuse. The mechanism of ulceration is thought to be due to the intense vasoconstrictive effect of cocaine, and usually affects the sites that directly come in contact with snorted cocaine, like the nasal and oral mucosa.Palatal and nasal mucosae are erythematous and edematous with changes, including deviation, excoriation, and perforation.Urine toxicological analysis for levels of cocaine and levamisole. p-ANCA-HNE is absent in CIMDL and differentiate lesions associated with levamisole from those resulting from isolated cocaine abuse.Secondary infection and aspiration.Cartilage or bone grafting and reconstruction.Pentazocine -induced skin ulcersPentazocine belongs to the group of drugs called narcotic analgesics and is a drug with a very high addiction potential. Pentazocine is believed to cause ulcers by vasoconstriction with tissue ischemia at injection sites, vessel trauma from repeated injections, and inflammatory response to precipitated pentazocine in tissues.Punched -out ulcers, usually distributed on accessible sites if self-injected, can also be present on the buttocks if injected by others. The ulcers are surrounded by hyperpigmented, sclerotic skin. Such ulcers on the extremities can lead to puffy hand and feet appearance because of the lymphedema distal to the fibrotic constrictions. Usually associated with thrombosed and fibrosed superficial veins.Urine toxicological analysis for levels of pentazocine.Secondary infectionWound care, debridement, drainage, skin grafts, and amputation.ANCA, Anti-neutrophilic cytoplasmic antibodies; cANCA, cytoplasmic ANCA; CIMDL, Cocaine-induced midline destructive lesion; HNE, human neutrophil elastase; LINES, levamisole-induced necrosis syndrome; pANCA, perinuclear ANCA; PR-3, proteinase-3. Open table in a new tab ANCA, Anti-neutrophilic cytoplasmic antibodies; cANCA, cytoplasmic ANCA; CIMDL, Cocaine-induced midline destructive lesion; HNE, human neutrophil elastase; LINES, levamisole-induced necrosis syndrome; pANCA, perinuclear ANCA; PR-3, proteinase-3. To conclude, xylazine adulteration/contamination should be kept as a differential diagnosis when evaluating patients presenting with cutaneous ulcers in setting of suspected illicit drug use. As there continues to be a global increase in illicit drug usage, dermatologists can expect to see a rise in mucocutaneous stigmata of drug abuse, and therefore, a knowledge of key clinical features and differentials will be helpful. None disclosed.