Cutaneous Allodynia Associated With GLP-1RA Tirzepatide for Weight Management: A Case Series

Introduction

Cutaneous allodynia is defined as pain caused by a non-noxious stimulus to normal skin that may not have elicited pain sensation in a normal state [1–3]. Allodynia is classified according to the sensory modality, such as dynamic mechanical, static mechanical, and thermal [4], and is commonly reported as burning sensation to touch, such as sunburn, inflammation, or trauma, or thermal allodynia as pain sensation to cold.

Tirzepatide is widely prescribed for the treatment of diabetes mellitus and for the management of obesity. With the attributes of dual-binding to glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors [5], tirzepatide is highly effective in glycemic control and has significant efficacy in the treatment of obesity [5,6].

Although hypersensitivity and injection site reactions were the only dermatological adverse events (AEs) reported in the tirzepatide prescribing information in the United States [7], a recent pharmacovigilance analysis of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database with 6 glucagon-like peptide-1 receptor agonists (GLP-1RAs), including tirzepatide, revealed several additional AEs. One of the reported AEs was allodynia, although rare in incidence [8,9]. However, limited case-level descriptions of tirzepatide-associated allodynia are currently available.

There are no known pharmacological mechanisms for allodynia in association with tirzepatide. However, recent studies demonstrate the activation of GLP-1RAs in the central nervous system, which may influence the altered processing of pain through the central and peripheral nervous systems [10]. In this case series, we describe moderate-to-severe allodynia in 2 patients with severe obesity treated with tirzepatide for weight management. To the best of our knowledge, these are the first reports of allodynia associated specifically with tirzepatide therapy, beyond previously described dermatologic AEs, such as injection-site reactions, hypersensitivity, and urticaria.

Case Reports

CASE REPORT 1:

A 55-year-old woman with class III severe obesity treated with tirzepatide for 7 months presented with moderate allodynia. Her past medical history was significant for obesity (baseline body mass index [BMI], 42.93 kg/m³), hypertension, hyperlipidemia, prior bariatric surgery, long QT syndrome, and endometrial polyp. She was initially prescribed semaglutide 0.25 mg subcutaneously (SC) once weekly for weight management. Due to a lack of insurance coverage, she elected to self-pay for a GLP-1 receptor agonist and preferred tirzepatide. She was started on tirzepatide 2.5 mg SC once weekly. Over the subsequent 2 months, the dose was titrated to 7.5 mg SC weekly, and she was counseled regarding a whole-food, plant-based diet, behavioral modification, and exercise. During this period, the patient achieved a 3.9% reduction from baseline body weight, and no AEs were reported aside from mild constipation, for which no medication was prescribed.

At the 5-month follow-up, her body weight had decreased 4.7% from baseline. However, she reported mild fatigue and moderate allodynia (Table 1), which had initially developed as mild symptoms at the 5 mg dose but had not been reported at that time and increased in intensity following escalation to 7.5 mg. The allodynia was localized to the dorsum of the upper and lower extremities, which was unrelated to the injection site and described as a sunburn-like sensation. The allodynia occurred on the day of the weekly injection and lasted approximately 1 day; however, it did not present with every dose. The allodynia was sensitive to touch, with a pain scale of 4 on a 10-point Likert scale. No alleviating factors were identified other than avoidance of tactile contact with the affected areas. She had no injection-site reactions or other dermatologic manifestations, including urticaria, rash, or pruritus. No medication was prescribed for the allodynia.

Despite the symptoms, the patient elected to continue tirzepatide at 7.5 mg weekly. At a subsequent follow-up visit 2 months later, there was no change in the patient’s weight, and the allodynia persisted. Given the persistence of this AE, her stable body weight, and an upcoming cataract surgery, she discontinued tirzepatide and opted to continue weight management through diet and exercise. The allodynia resolved completely after discontinuation of the medication, without specific treatment (Table 1).

Relevant laboratory investigations at baseline and following initiation of tirzepatide therapy demonstrated normal renal and hepatic function. Serum potassium, calcium, thyroid-stimulating hormone, complete blood count with differential (including eosinophils), and hemoglobin levels were all within the reference range. Serum vitamin B12 levels remained within the reference range after the onset of allodynia. Although the patient had vitamin D deficiency at baseline, serum vitamin D levels remained stable following the development of allodynia. The pre-treatment glycosylated hemoglobin (HbA1c) was 5.7%, which improved to 5.4% at the time of tirzepatide discontinuation (Table 2).

The Naranjo Adverse Drug Reaction Probability Scale score was calculated by the prescribing physician as 7/10 (probable), based on the temporal relationship between tirzepatide initiation and the onset and frequency of the adverse event, resolution following drug discontinuation, absence of relevant comorbidities, and lack of concomitant medications known to cause allodynia.

CASE REPORT 2:

A 46-year-old man with class I obesity treated with tirzepatide for 8 months presented with severe allodynia. His past medical history was notable for obesity (baseline BMI, 34.67 kg/m³), hypertension, and secondary male hypogonadism. He was initially prescribed semaglutide 3 mg SC weekly for weight management, which was titrated to 14 mg over the subsequent 3 months. However, due to suboptimal weight reduction, he preferred switching to tirzepatide after discussion with his healthcare provider and was prescribed tirzepatide 2.5 mg SC weekly. The dose was titrated from 2.5 mg to 12.5 mg over the ensuing 5 months and was efficacious, resulting in a 12.9% reduction in body weight from baseline, without AEs. The patient continued 12.5 mg weekly and achieved further weight loss (16.3% from baseline) over the following 2 months.

At the 7-month follow-up visit, the tirzepatide dose was increased to 15 mg weekly. During that month, the patient developed an upper respiratory tract infection with fever and tested positive for influenza; symptoms persisted for approximately 1 week, while the patient withheld tirzepatide administration. After recovery, he resumed tirzepatide 15 mg SC weekly. On the day following injection, he developed a sunburn-like sensation over the left upper extremity, which progressed to whole-body severe, generalized allodynia (Table 1). The pain was exacerbated by light touch, particularly contact with clothing or bedding, especially when rubbing with a blanket, and was rated 8 on a 10-point Likert scale. The patient did not have any other dermatological manifestation, including skin rashes, and he denied having any injection site reaction, fever or chills, or gastrointestinal (GI) symptoms. Symptoms were alleviated with diphenhydramine, and no additional medications were prescribed. He also reported a transient “freezing” sensation that appeared unrelated to the allodynia. Notably, he did not experience cutaneous pain or allodynia during the preceding influenza illness.

Symptoms gradually subsided over the subsequent days, and tirzepatide was discontinued, after which the allodynia resolved completely (Table 1). No additional pharmacological therapy was required. Despite this adverse event, the patient elected to resume tirzepatide, and a lower dose of 5 mg SC weekly was prescribed after 2 months. The dose was gradually escalated to 12.5 mg over the next 6 months, without recurrence of allodynia or other dermatologic or sensory AEs. The patient is currently maintained on tirzepatide at a dose of 15 mg SC weekly.

Relevant laboratory evaluations at baseline and following initiation of tirzepatide demonstrated normal renal and hepatic function. Serum potassium, serum calcium, thyroid-stimulating hormone, complete blood count with differential (including eosinophils), and hemoglobin levels were within the reference range. The patient’s HbA1c, serum vitamin B12, and vitamin D levels were also within the reference range at baseline; subsequent assessments were not performed (Table 2).

According to the prescribing physician, the Naranjo Adverse Drug Reaction Probability Scale score was calculated as probable (5/10), based on the temporal association of the AE with a higher dose of tirzepatide, resolution following drug discontinuation, and the absence of alternative concomitant medications. The recent occurrence of influenza was considered and quantified as a potential alternative etiology for allodynia during calculation of the Naranjo score in this patient.

Discussion

Tirzepatide, a dual agonist for GLP-1 and GIP receptors [5], is widely prescribed for management of diabetes mellitus, as well as for obesity or weight management. Tirzepatide’ s dual agnostic and synergistic mechanisms involving GLP-1 and GIP lead to its superior efficacy in glycemic control, lipid reduction, and treatment of type 2 diabetes mellitus, as well as to its potent activity in rapid weight loss [6]. The results of the SURPASS 1 to 5 trials demonstrated superior efficacy of tirzepatide compared with placebo and other commonly used glucose-lowering medications, such as semaglutide, dulaglutide, insulin degludec, and glargine, with substantial reductions in body weight [11]. All doses of tirzepatide were well tolerated, with similar AE profiles to that of the GLP-1 receptor analogs [11]. GI toxicity made up the major AEs, with nausea, diarrhea, and vomiting being most common AEs associated with tirzepatide [12]. Subsequently, the SURMOUNT-4 randomized clinical trial also exhibited mild-to-moderate GI toxicities as the common AEs [13].

The U.S. prescribing information for tirzepatide described hypersensitivity and injection site reactions as the only reported dermatological AEs [7]. However, a recent pharmacovigilance analysis demonstrated several additional dermatologic AEs with tirzepatide, including allodynia, although rare in incidence [8,9]. In the present case series, we report moderate-to-severe allodynia in 2 patients with severe obesity receiving tirzepatide for weight management, which, to the best of our knowledge, is the first description of allodynia specifically associated with tirzepatide therapy.

Other commonly observed toxicities associated with GLP-1RA are GI AEs and, less commonly, serious AEs, such as injection site reactions, hypotension, pancreatitis, pancreatic cancer, thyroid cancer, cholelithiasis, hepatotoxicity, acute kidney injury, angioedema, and syncope, which have all been described [14–18]. While data from several studies suggested associations between GLP-1RAs and various neurological adverse events (NAEs) [8,9], direct casualty and the relationship of NAEs has not been clearly established with GLP-1RA. Interestingly studies suggest GLP-1RAs may have neuroprotective effects and could potentially treat diabetic peripheral neuropathy by modulating inflammation and oxidative stress, as well as potentially through mechanisms such as enhancing Na+/K+-ATPase pump activity and promoting nerve growth and myelin [19,20].

GLP-1RAs are associated with various dermatologic effects, ranging from mild injection site reactions to more complex immune mediated responses, such as hypersensitivity, urticaria, and bullous pemphigoid [21]. Dysesthesia, paresthesia, hyperesthesia, and neuralgia were reported earlier with GLP-1RAs, particularly with semaglutide [22,23]. In a recent report, Chen et al described a pharmacovigilance analysis of the FAERS database (2005 Q2 to 2024 Q3) evaluating NAEs associated with 6 GLP-1RAs, exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, and tirzepatide [9]. Among 28 953 NAE reports associated with GLP-1RAs, the reporting odds ratio (ROR) quantifies the relative association of a specific AE report to a target drug compared with its reporting frequency with all other drugs in the FAERS database [24,25]. Based on disproportionality analysis, 19 distinct NAE signals were identified, including dizziness, tremor, dysgeusia, lethargy, taste disorder, presyncope, parosmia, allodynia, and hypoglycemic unconsciousness [9]. Allodynia, although reported infrequently, had the highest ROR (95% CI): 22.55 (21.71–30.08), compared with other NAEs whose ROR values were in single digits. It is also noteworthy to mention that higher NAE proportions were reported with semaglutide and exenatide (16.97% and 14.44%, respectively) compared with tirzepatide (6.06%). A similar pharmacovigilance analysis of NAEs in the FAERS database also reported the higher incidence and ROR of sensory-related AE with semaglutide relative to those with tirzepatide [8]. Indeed, most recently in a case series, Stark et al described 4 patients who experienced allodynia associated with dose escalation of semaglutide for management of obesity [26]. Here, we report 2 cases of allodynia associated with dose escalation of another GLP-1RA medication, tirzepatide.

Cutaneous allodynia is defined by the International Association for the Study of Pain (IASP) as a pain resulting from a stimulus that does not usually evoke pain in a steady state [1] and is classified as mechanical (dynamic or static) or thermal based on the characteristic of the pain [2,4]. Drugs that can cause or contribute to allodynia include chemotherapy drugs, such as oxaliplatin, taxane, or vinca alkaloids [27,28]; certain antibiotics, such as fluoroquinolones, metronidazole, and HIV/AIDS medications [28]; and opioids [29,30]. Chronic morphine therapy may sometimes paradoxically increase pain, and codeine and other opioids may be able to induce both hyperalgesia and allodynia, possibly by TLR4 activation-dependent proinflammatory cytokine release by glial cells [30]. Several concomitant clinical conditions have also been reported with allodynia, which include neuropathies and neuropathic pain, fibromyalgia, trigeminal and postherpetic neuralgia, migraine, multiple sclerosis, and osteoarthritis [31,32].

Among the 2 patients described in this case series, neither was prescribed with any concomitant medications that may cause allodynia, nor did these patients have comorbidities associated with allodynia. Relevant laboratory test results, including serum calcium, thyroid-stimulating hormone, and complete blood count with differential, including eosinophils, were within the reference range at baseline and after starting tirzepatide treatment (Table 1). Neither of the patients was diabetic, and their HbA1c levels were not overly increased to lead to complication of diabetic polyneuropathy. These patients were prescribed with the FDA-approved initial dose of tirzepatide 2.5 mg SC injection once weekly for their weight management program and gradually dose escalated according to the current standard of care and prescribing information [7]. Each patient reported allodynia after the initiation of tirzepatide treatment with dose escalation at higher doses (Figure 1). In fact, skin hypersensitivity and allodynia were earlier reported with semaglutide, also at higher dose levels [22,26]. Although the incidence of most of the AEs related to tirzepatide occurred within the first month (range, 7–90 days) of initiation of the medication, a recent pharmacovigilance analysis of tirzepatide in the FAERS database showed that about 3% of AEs occurred within or after 1 year of tirzepatide treatment [33], which corresponds with the incidence of allodynia in this case series (Figure 1). The locations of the skin sensitivity and allodynia in both patients were distinctly different from the injection site, including 1 patient with whole-body allodynia, which also clearly differentiates from the commonly reported injection site reaction associated with GLP-1RA.

At scheduled follow-ups, each patient in this case series reported allodynia described as a burning sensation and skin tenderness after tirzepatide administration. A 10-point Likert scale is used to assess pain in this case series, with 0 representing no pain and 10 being the worst pain reportable [34]. While this pain scale is not validated in all types of pain, including in allodynia, this was the pragmatic choice to use at the time of each patient’s report of the adverse reaction. Allodynia reported in these patients were mechanical in nature; the first patient had a static allodynia, localized on the dorsum of the upper and lower extremities, which was sensitive to touch. In contrast, the second patient had severe whole-body allodynia, which increased with moving objects over the skin, such as when rubbing with a blanket, demonstrating the dynamic allodynia. Interestingly, the second patient reported a concomitant freezing-like symptom, which was not associated with allodynia or temperature changes. Experiencing cold sensations has been described as a AE for individuals taking semaglutide and tirzepatide. Cold sensation is often attributed to reduced calorie intake, less body fat, and metabolic changes associated with GLP-1RA treatment. Central modulation of GLP-1 receptors in the ventromedial nucleus of the hypothalamus was attributed to sensation of altered body temperature and possibly mediated by specific inhibition of the energy sensor AMP-activated protein kinase [35,36]. This is distinctly different from the mechanistic basis of allodynia and should not be confused with thermal allodynia without any relationship to temperature change and altered skin sensation in this patient.

The assessment of Naranjo scores [37,38] was performed in both patients and indicated probable (total score, 5–8) association with the prescribed medication tirzepatide based on the initiation and frequency of the AE with the dosing, resolution after the discontinuation of the drug, and lack of other possible medications or comorbidities. In the first patient, mild allodynia first occurred on the day of weekly injections at 5 mg and increased in intensity at 7.5 mg. There were no other comorbidities nor any symptoms before or after the incidence of this AE, which further confirms the association of allodynia with tirzepatide treatment. The second patient experienced whole-body severe allodynia only once after a dose at 15 mg of tirzepatide. The AE was alleviated with diphenhydramine, and the allodynia was resolved with the discontinuation of tirzepatide. However, the patient had influenza symptoms 1 week prior to the incidence of this AE, and the implication of this viral infection, although small, could not be ruled out. While assessing the Naranjo score in this patient, the probable association of influenza was quantified as a potential etiology for the symptoms. There were no other comorbidities or concomitant medications, and the temporal association with dose escalation of tirzepatide and resolution of allodynia after termination of the drug led to the Naranjo scoring of probable for this patient. It is noteworthy that the patient did not experience allodynia or any other dermatological symptoms during flu infection.

Hypersensitivity and injection site reactions were described as the only dermatological AEs in the U.S. prescribing information [7], as well as in Phase 3 clinical trials with tirzepatide (SURPASS 1–5 and SURMOUNT), which include injection site reactions ranging from 2% to 3% and hypersensitivity in 2% to 4% patients, respectively [39–44]. Of note, an analysis of tirzepatide in the FAERS database did not specifically emphasize the association of allodynia with this drug [33].

There is currently no clear pathopharmacological evidence supporting a mechanism for allodynia in association with tirzepatide. Altered skin sensations, including dysesthesia, paresthesia, hyperesthesia, burning sensations, and allodynia, were described with semaglutide [22,26]. The mechanisms underlying these skin adverse reactions remain unclear; however, recent studies have described the activation of GLP-1 receptors in the central nervous system that may influence the altered processing of pain through the central and peripheral nervous systems, possibly through metabolic and vascular pathways [45–47]. It was also documented that rapid weight loss induced by GLP-1RAs could lead to shifts in fat distribution, potentially affecting the skin’s sensory nerves, leading to sensations of burning or tingling [23,47]. In addition, activation of GLP-1 receptors located in the brainstem and hypothalamus may further influence the pain modulation and altered skin sensitivity [48]. Earlier studies have indicated the direct modulation of central pain pathways by GLP-1RA therapies in patents with fibromyalgia and chronic lower back pain [49]. Most importantly, the effect of GLP-1RA was implicated in central sensitization by recruiting previously subthreshold synaptic inputs to nociceptive neurons, thereby generating an increased or augmented action potential output, which may produce pain hypersensitization so that even innocuous input can produce augmented pain sensation, which in a normal state may not produce pain [10]. This proposed mechanism of neuronal sensitization is highly pertinent to GLP-1RA–associated skin pain and allodynia.

Conclusions

In this case series, we report allodynia in 2 patients with severe obesity who were treated with tirzepatide for weight management. Although dermatologic AEs, such as injection site reactions, hypersensitivity, and urticarial, were reported earlier, to the best of our knowledge, this is the first case series reporting allodynia specifically with tirzepatide therapy. The incidence of allodynia was temporally associated with dose escalation, occurred at higher doses, and resolved after termination of the drug, supporting a probable association with tirzepatide treatment. Indeed, assessment of Naranjo scores demonstrated a probable association with the tirzepatide based on the initiation and resolution of the AE and the lack of other possible medications or comorbidities. These findings should be interpreted with caution due to the small sample size, absence of a control group, and potential confounding factors, particularly in the second patient, who had an intercurrent infection and prior semaglutide exposure. Furthermore, the limitations of applying the Naranjo scoring system in this context must be acknowledged. One patient resumed tirzepatide treatment at a lower dose several months after discontinuation without recurrence of allodynia, indicating the need for further exploration of dose escalation and dose adjustments during tirzepatide treatment for weight management to mitigate AEs, such as allodynia. At present, no well-defined pharmacological mechanisms have been established to explain the association between tirzepatide and allodynia. However, emerging evidence indicates that activation of GLP-1 receptors within the central nervous system may modulate pain processing pathways. Such activation could alter central and peripheral nociceptive signaling through neuronal sensitization and central neural plasticity, thereby contributing to pain hypersensitivity. Since allodynia is also reported with semaglutide, prescribers should be aware of this specific AE with the GLP-1RA class of compounds, especially when using higher doses for weight management.