A case of overdose via tattoo

Case report

A 56-year-old male was brought by ambulance to the emergency department having been found at home by his friend to be drowsy and cyanosed. His past medical history included type 2 diabetes mellitus, hypertension, bipolar depressive disorder and chronic back pain. Regular medications were aspirin 75 mg mane, atorvastatin 40 mg mane, citalopram 20 mg mane, fentanyl transdermal patch 100 mcg 72 hourly, human insulin 16 units mane and 14 units nocte, metformin 1G bd and sodium valproate 500 mg mane and 1 g nocte. He was also prescribed as required tramadol 100 mg and naproxen 250 mg.

On examination there was a patent airway, respiratory rate of 12 breaths per minute, peripheral oxygen saturations of 92% breathing room air. Blood pressure was 110/75 mmHg, heart rate of 83 beats/min and temperature 36.7 ℃. His Glasgow Coma Score was fluctuating between E2 V3 M5 and E3 V5 M6 at best. Pupils were 2 mm bilaterally and reactive to light and capillary blood glucose 11.4 mmol/l. He was also acidotic with a pH of 7.24 and PaCO₂ of 9.03 (BE –0.2 mmol/l, HCO₃ 28.6 mmol/l).

A collateral history from the patient's friend was obtained: the patient had been completely well the evening before the incident; he had become intermittently confused on the afternoon when she found him and had called for an ambulance as he became increasingly drowsy and blue around the lips. She denied witnessing any seizure-like activity, the use of recreational drugs or deliberate overdose. The patient had a similar presentation to the Emergency Department six months previously, with normal findings on an EEG, CT brain and lumbar puncture. At the time he was found to have mistakenly applied a second fentanyl patch, without removing the old one, and was diagnosed with a probable inadvertent overdose of fentanyl after excluding other possible causes.

In the Emergency Department, the patient regained full consciousness after 800 mcg of naloxone. Minutes later he dropped his level of consciousness and had decerebrate posturing, fixed downward gaze and bilateral limb jerking. Suspecting a seizure, he was given 2 mg of lorazepam and loaded with phenytoin. The jerking stopped but the patient remained comatose and tolerated an oropharyngeal airway. The patient was intubated and ventilated for airway protection. A CT brain was normal. Empirical treatment with ceftriaxone and acyclovir was started for possible encephalitis. The patient was transferred to the intensive care unit and remained sedated and ventilated until the following morning. Routine admission blood tests were normal. Urine drug screen was negative for opioids, positive for barbiturates and benzodiazepines (reflecting drugs given in hospital).

The following morning sedation was stopped; the patient woke up appropriately and was extubated. He reported having no memory of the morning leading up to the admission. Given the recent history of inadvertently placing two fentanyl patches, the patient was thoroughly assessed and questioned about the patch placement. He was adamant that he had placed one fentanyl patch over his left upper arm. He had a fresh-looking tattoo over this site (Figure 1), which on further questioning turned out to be only five days old. This led to a suspicion of opiate toxicity secondary to an increased absorption of fentanyl through the broken and inflamed skin that had recently been tattooed. OPEN IN VIEWER

Pharmacological properties of transdermal fentanyl

Fentanyl is a pure mu-opioid receptor agonist, which is approximately 75–100 times more potent than morphine. ² Unlike morphine, fentanyl has extensive first-pass hepatic metabolism limiting its oral bioavailability and making this route ineffective.^2,5 Absorption is however successful via the oral mucosa in the form of a lozenge or lollypop and the nasal mucosa by intranasal spray. It has been suggested that fentanyl was used in a vapourized form by Russian forces to disable armed Chechens who had seized the crowded Dubrovka theatre in Moscow on 23 October 2002. ⁶

Fentanyl's low molecular weight (337 Da) and its solubility in both lipid and aqueous conditions provide it with the essential physical and chemical properties required for transdermal use. ² The high lipophilicity of fentanyl enables its rapid diffusion through the keratinaceous stratum corneum past the ceramides and other waxy lipids of this layer. This is followed by a slower movement through the water-rich dermal tissue before it is absorbed systemically, resulting in the formation of a ‘fentanyl depot’ in the epidermis. This accounts for the initial slow onset and the prolonged effects of transdermal fentanyl,^2,7 which has a mean half-life of 20–27 h after patch removal, compared to the 3–12 h after an IV infusion. ⁸

A number of studies have described the variability in the rate of absorption through different skin types and conditions. Experimental studies have shown a fivefold increase in serum fentanyl concentration following application of a transdermal fentanyl device on broken skin compared to intact skin. ⁹ An in vitro experiment on cadaver skin demonstrated a >30-fold increase in fentanyl absorption rate when applied on exposed tissue lacking a stratum corneum. ¹⁰ Other studies identified that heat and/or elevated skin temperature increased the absorption of transdermal fentanyl, probably secondary to vasodilation of cutaneous vasculature.^11–13 In addition, many case reports have described a potential or actual fentanyl overdose following exposure to external heat sources including hot tubs, heating blankets, saunas and sunbathing.^13–15

As transdermal fentanyl administration avoids first-pass hepatic metabolism, it achieves an excellent bioavailability (∼92%), most of which is protein bound (84%). Fentanyl's high lipid solubility contributes to its large volume of distribution (∼ 6 l/kg)² and rapid crossing of the blood–brain barrier. Fentanyl is a weak base (pKa = 8.4) ⁸ and is affected by changes in pH as explained by the Henderson–Hasselbalch equation for a weak base

p K a - pH = log 10 [ B H + B ]

Fentanyl is metabolised primarily by hepatic cytochrome P450 3A4, to norfentanyl and other inactive metabolites through an oxidative N-dealkylation process, making it susceptible to drug interactions. ² For instance, the concomitant use of fentanyl with cytochrome P450 3A4 inhibitors (e.g. fluconazole, verapamil, amiodarone, diltiazem, clarithromycin) may decrease the clearance of fentanyl and therefore increase its plasma concentration and the risk of adverse drug effects. The inactive metabolites are excreted in urine and a small amount (10%) of fentanyl is eliminated unchanged. ⁸ However, because of its structural dissimilarity, fentanyl does not produce a positive result on the opioid/opiate component of a standard immunoassay-based ‘urine drug screen’. ² Instead, a more analytical and specific method involving liquid or gas chromatography–mass spectrometry is the established standard for measuring serum or urine fentanyl concentrations, ² which may explain why the urine drug screen was negative for opioids in our patient.

The physiology of tattooing

Notable and predictable physiological changes occur in the tattooed skin particularly in the first two weeks. Tattooing involves the repeated piercing of the skin with needles to a depth of 1–2 mm, to deliver pigments into the dermis, causing the permanent imprint of a design. ¹⁶ The pierced skin becomes erythematous, and the activated immune response results in dermal and epidermal oedema, visible externally as induration. During the first few days, the healing tattoo responds similar to a sunburn, with dermal inflammation and infiltration of phagocytes, causing the initial sloughing of the overlying epidermis, leaving only the pigment within the deeper dermis. ¹⁶ This is engulfed by phagocytes which remain localised within granulating tissue and later converted to connective tissue by collagen growth. ¹⁷

The skin hosting a fresh tattoo comprises two significant physiological changes that may increase the rate of absorption of a transdermal drug:

A damaged or partially removed stratum corneum by the repeated injection of micro-needles;

To our knowledge, this is the first reported case of transdermal opioid toxicity via tattoo, for which reason we have reported our concerns to the MHRA using the YellowCard Scheme. As the use of fentanyl patches become more widespread, we believe it is important that both prescribers and users are alerted of this rare, but potentially serious safety concern.

Patient consent

Written consent was obtained from the patient.