Cutaneous effects of drugs of abuse

What is drug abuse?

Abuse of addictive substances, including prescription medications, is a complex, serious issue which contributes to significant disease, injury, illness, violence, crime, social, community safety, and family issues [1]. Substance abuse disorders can vary between occasional hazardous use and severe disorders of dependency.

• Cutaneous manifestations can be the earliest identifiable signs of substance abuse and related systemic diseases.
• Substance abuse in patients with chronic disabling skin conditions can be in response to embarrassment and feelings of rejection, stigma, and low self-esteem, or as a means of relieving pruritus.

This review discusses alcohol, methamphetamine, cocaine, cannabis, illegal and pharmaceutical opiates, and commonly associated co-morbidities.

Drug use in Australia

According to the 2016 National Drug Strategy Household Survey (NDSHS), young adulthood (18–29 years) is a high-risk time for the use and misuse of licit and illicit substances, relative to other age groups. People living in remote and very remote areas were more likely to smoke, drink at harmful levels, and use cannabis and methamphetamines, but less likely to use illicit drugs such as cocaine and ecstasy compared with those in major cities.

In 2011, alcohol was responsible for 5.1% of the total burden of disease and injury in Australia, and illicit drug use contributed to 1.8% (AIHW 2016). This included the impact of injecting drug use, and cocaine, opioid, amphetamine, and cannabis dependence.

Alcohol

Alcohol abuse and dependence are common and the second highest cause of preventable drug-related hospitalisation and mortality in Australia. One study reported that 34.7% of patients who attend Australian public hospital outpatient departments were identified as having unhealthy levels of alcohol consumption [2]. The NDSHS reported a decline in daily alcohol consumption between 2013 (6.5%) and 2016 (5.9%). However, the proportion of people binge drinking did not change. Ninety per cent of Australians have had alcohol in their lifetime, with about a quarter drinking at levels associated with increased risk of long term harm [3].

Alcohol is a legal sedative-hypnotic class of drug that impairs motor function and coordination, decision-making, and judgement. It affects the nervous system through the facilitation of inhibitory pathways (GABA) and inhibition of excitatory pathways (NMDA) [4]. A careful history is required to elucidate alcohol consumption to determine alcohol misusers and alcohol dependency.

Every drink above two standard drinks a day increases the lifetime risk of disease and injury. Physical harms include direct physical injury from risk-taking behaviour, excessive sedation, inflammation of the gastrointestinal tract, alcoholic liver cirrhosis, pancreatic inflammation, nutritional deficiencies, cognitive impairment, rhythm and structural disorders of the heart, and altered immunity [5–7].

Cutaneous manifestations of chronic liver disease and cirrhosis associated with alcohol

Cutaneous changes can occur at any stage of alcohol abuse.

Cutaneous changes due to nutrient and vitamin deficiencies with excessive alcohol

Malnutrition in those dependent on alcohol is multifactorial. The most common vitamin deficiency is vitamin B1 (thiamine), which presents as Wernicke-Korsakoff syndrome in the later stages of alcohol dependence [9].

Psoriasis

There is a complicated relationship between alcohol consumption and psoriasis. Two patterns have been identified in patients who misuse alcohol.

• Flat hyperkeratotic, erythematous plaques over the acral surfaces.
• Inflammatory plaques with minimal scale involving the face, groin, and flexures.

Porphyria cutanea tarda

Porphyria cutanea tarda results from a complex interaction between inherited and acquired factors, including alcohol-induced liver damage. It presents as hemorrhagic bullae, crusting and scarring in sun-exposed areas due to a defect in uroporphyrinogen decarboxylase. This leads to the accumulation of porphyrins that cause photosensitivity.

Rosacea

A variety of factors are responsible for the different presentations of rosacea (flushing, papules and pustules, rhinophyma, and tissue hyperplasia) [10].

• Alcohol causes erythema and flushing due to cutaneous vasodilation and pro-inflammatory effects.
• A large cohort study demonstrated that alcohol intake (especially white wine or liquor) is significantly associated with an increased risk of rosacea in women in a dose-dependent manner [11].
• Collagen III propeptide is increased in patients with high alcohol consumption, providing a clue to the mechanism of tissue hyperplasia in late-stage rosacea [12].

Discoid eczema

Localised and well-demarcated plaques of acute exudative discoid eczema on the shins of middle-aged men can indicate alcohol misuse [13].

Increased skin infections

Alcohol-induced immune dysfunction facilitates colonisation by commensal organisms and an increased incidence of cutaneous infections [14].

Seborrhoeic dermatitis

There is a very strong association between the incidence and severity of seborrhoeic dermatitis and alcohol consumption [14].

Cancer

High intake of alcohol is associated with squamous cell carcinoma of the skin, mouth, and oropharynx, as well as hepatocellular carcinoma, pancreatic carcinoma, and breast cancer in women [13]. Basal cell carcinomas may be more aggressive, more likely to be infiltrative, and exhibit a higher incidence of local recurrence [3].

Methamphetamine

Methamphetamine, also known as meth or ice, is manufactured from pseudoephedrine, ephedrine, acetone, ammonia, and ethylene glycol. Crystal methamphetamine is now the third most common illicit substance used in Australia, after cannabis and cocaine [15]. Its use increased from 22% of recent meth/amphetamine users in 2010 to 57% in 2016. The overall use of ice across the population rose from 0.4% in 2010 to 0.8% in 2016, with over 200,000 current users in 2015. Over half of those who use methamphetamine meet criteria for dependent use [16].

Methamphetamine is commonly smoked, injected, or snorted. It is a sympathomimetic agonist that acts centrally to release dopamine and other biogenic monoamines from their storage sites in the nerve terminals to produce rapid euphoria, central nervous system (CNS), cardiovascular, and smooth muscle effects. Immediate effects include increased energy, concentration, tachycardia, fluctuant blood pressure, hyperhidrosis, mydriasis, bruxism, generalised pruritus, xerosis, and compulsive skin picking [17].

Prolonged use results in:

• Cardiovascular effects including hypertension, tachycardia, and direct myocardial toxicity resulting in arrhythmias, malignant hypertension, haemorrhagic stroke, cardiac ischaemia, cardiomyopathies, and right heart failure [18]
• Mood disorders, psychosis, cognitive impairment, and cortical grey matter loss [19]
• Malnutrition, weight loss, and premature ageing
• Dental decay, due to a combination of vasoconstriction, poor dental hygiene, consumption of high-calorie sugar drinks, and xerostomia [20,21]
• Neurotic excoriations and abscess, most commonly on limbs [22].

Cocaine

Cocaine is also known as rack, blow, Charlie, coke, snow, or flake is a sympathomimetic that causes feelings of euphoria, increased confidence, and well-being. Cocaine is extracted from the Erythroxylum coca plant into a water-soluble powder that is usually inhaled (snorted), ingested, or injected. Its short-term effects include tachycardia, hypertension, altered mental status, and mydriasis [23,24].

The use of cocaine in Australia has increased from 1.3% in 2001 to 2.5% in 2016. It is the second most commonly used illegal drug after cannabis [16]. Australians are the world’s eighth-highest per capita users of cocaine. Nine per cent of Australians aged 14 years and over have used cocaine one or more times in their life, and its use is increasing with casual users as well as dependent and frequent users [1,3].

Cutaneous effects include:

• Urticarial vasculitis
• Eosinophilic granulomatosis with polyangiitis
• Necrotising granulomatous vasculitis
• Palpable purpura due to other forms of cutaneous vasculitis
• Buerger disease
• Delusions of parasitosis and neurotic excoriations [23]
• Stevens-Johnson syndrome and acute generalised erythematous pustulosis [25]
• Necrosis and perforation of the nasal septum.

Many adverse effects in relation to cocaine use are linked to ‘expanders’ or cutting agents that are mixed with cocaine to increase profitability for dealers [27]. According to the 2015 Illicit Drug Reporting System, the purity of cocaine seized in Australia ranged between 29.9% and 64.5%, and in Sydney, between 9% and 40% [28]. Common adulterants and cutting agents include talc, mannitol, glass, starch, quinine, lignocaine, amphetamine, caffeine, heroin, scopolamine, hydroxyzine, diphenhydramine, and levamisole [26].

Levamisole has been identified in Australian street cocaine, and unlike other cutting agents, it is added at the onset of manufacturing. Levamisole potentiates the effects of cocaine and increases dopamine levels. It is an antiparasitic medication used for livestock and was removed from human therapeutic use due to neutropenia, agranulocytosis, and vasculitis. Vasculitis from cocaine mixed with levamisole presents as distinct purpuric lesions involving the external pinna and cheeks [28].

Cannabis

Cannabis is a psychoactive drug from the dried buds and flowers of the Cannabis sativa plant. In Australia, it is also known as ganja, yarndi, weed, and dope. Cannabis is usually smoked in hand-rolled cigarettes (a ‘joint’) or a water-pipe (a ‘bong’). Cannabis can also be added to foods for consumption. It is the most common illicit drug in Australia, with over one-third of Australians aged 14 years and over having had used cannabis at least once in their lifetime [15].

Its psychoactive properties are derived from the chemical compound delta-9-tetrahydrocannabinol (THC) among other compounds that target cannabinoid receptors in the brain to produce euphoria and heightened senses. This activation of the cannabinoid receptors leads to a reduction in nitric oxide that causes systemic vasoconstriction.

• Vasoconstriction may present as claudication, Raynaud phenomenon, peripheral necrosis (blue toes), and ulcers of distal extremities (like Buerger disease) [29,30].
• Other cutaneous manifestations include premature ageing with periorbital darkening, hair loss, and greying of hair [31].

Non-psychotropic phytocannabinoids derived from Cannabis sativa have demonstrated sebostatic, anti-inflammatory and antiproliferative mechanisms and have pharmacological potential in the treatment of acne, pruritus, various inflammatory skin diseases, and skin cancer [32].

Opioids

Pharmaceutical opioid-related deaths, overdoses, and emergency presentations exceed those related to illicit heroin [1].

Drugs of the opioid class can either be naturally occurring, or synthetic. The actions of these substances are mediated through agonism of mu, kappa, and delta-opioid receptors [33].

• Pharmaceutical opioids include morphine, hydromorphone, codeine, fentanyl, and oxycodone.
• They are usually ingested orally or crushed and snorted intranasally or dissolved and injected intravenously.
• Tolerance and physical dependence develop upon repeated administration of opiate medications with a high potential for abuse and the development of a strong physiological dependence.
• Long-acting opioids such as methadone and buprenorphine improve outcomes in patients with opioid dependence.

Acute opioid toxicity results in stupor and respiratory depression.

• Chronic use of opioids can cause orthostatic hypotension, nausea and vomiting, constipation, and potential faecal impaction.
• Long-acting opioids have been implicated in causing central sleep apnoea.
• High doses of methadone are associated with prolonged QT and subsequent risk of torsades de pointes.
• Opioids influence the hypothalamic-pituitary-adrenal or gonadal axes. This can result in an increase in serum prolactin and a decrease in plasma cortisol and testosterone (male hypogonadism) [34].

Dermatological manifestations of opioid use may include:

• Urticaria
• Hyperhidrosis [34]
• Morbilliform eruption
• Glucagonoma-like syndrome (necrolytic migratory erythema)
• Acanthosis nigricans [26,31,35].

The symptoms of opioid withdrawal resemble a 'flu-like illness with myalgia, rhinorrhoea, nausea and vomiting, lacrimation, piloerection, insomnia, dilated pupils, irritability, low-grade fever, and tachycardia [33].

Injection-related cutaneous signs

Track marks at injection sites present as linear postinflammatory hyperpigmentation, most commonly observed in the antecubital fossa of the non-dominant arm. Other common injection sites include the veins of the dorsum of the hands and feet, forearm, popliteal fossa, inguinal fold, neck, and penis [26,35,36].

• Tattoos may be used to conceal the track marks.
• Over time, the injection sites become thickened, sclerosed, and inaccessible.
• Some drug users resort to intradermal, subcutaneous, or even intramuscular drug administration (‘skin popping’) resulting in irregular, white, deep circular, punched-out atrophic scars [35].
• Foreign body granulomas can form at the injection site due to additives such as plastic, glass, talcum, mannitol, starch, or flour [37].

Vascular complications may include:

• Superficial thrombophlebitis and deep venous thrombosis
• Chronic venous insufficiency including peripheral oedema and venous eczema
• Arterial insufficiency, necrosis, thromboembolism, and compartment syndrome due to accidental or purposeful arterial injections  [35,36].

Skin and soft tissue infections

Drugs of various types may be dissolved in tap water by a drug abuser, drawn into a syringe and injected into a vein or skin. Infectious complications of non-sterile injection include abscess, cellulitis, and erysipelas. Contributing factors are:

• The contamination of drug with expedients
• The use of non-sterile water, needles, or equipment
• The re-use of needles
• Skin popping — this carries a five-fold risk of infection compared to intravenous injection resulting in a multilobulated, deep and necrotic abscess [37]
• Immunosuppression due to blood-borne viruses (such as human immunodeficiency virus, HIV)
• Malnutrition
• The specific drug — infection is especially likely when injecting a mixture of heroin and cocaine, known as ‘speedball’.

Skin and soft tissue infections are often multibacterial and due to commensal pathogens, commonly Staphylococcus aureus, Streptococcus milleri and alpha-haemolytic streptococci. The practice of licking or blowing out the injection needle before injection increases the risk of infection with resident oral flora, gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Proteus vulgaris, Klebsiella, Haemophilus) and anaerobic species (Bacteroides, Fusobacterium, Eikenella corrodens) [38]. Patients present with large indurated abscesses.

Most patients with injection-site infections have normal inflammatory markers and negative blood cultures.

Other infections

People who misuse substances are at an increased risk of blood-borne infectious diseases such as HIV, hepatitis B, and hepatitis C, and sexually transmissible infections such as syphilis, gonorrhoea, infections with Chlamydia trachomatis (lymphogranuloma venereum), Trichomonas vaginalis (trichomoniasis) and Herpes simplex 1 and 2 [39].

Scabies, tinea, and impetigo contagiosa are frequently observed in those who are homeless or living in situations of neglect. Clinicians should also be mindful of signs and symptoms of endocarditis.