Noticeable changes in diaphoresis severity following pain management medication adjustments in a complex regional pain syndrome patient

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Anesth Pain Med. 2025;20(1):72-77

Publication date (electronic) : 2025 January 25

doi : https://doi.org/10.17085/apm.24174

Joon Hee Lee¹, Eun Joo Choi¹, Pyung-Bok Lee^,1,2

¹Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

²Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Korea

Corresponding author: Pyung-Bok Lee, M.D., Ph.D. Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: 82-31-787-7499 Fax: 82-31-787-4063 E-mail: painfree@snubh.org

This study was presented in the 78th Korean Pain Society Meeting, on 16 November, 2024.

Received 2024 December 4; Revised 2024 December 20; Accepted 2024 December 31.

Abstract

CASE REPORT

A 24-year-old woman presented to the clinic in August 2019 with tingling pain in her left ankle, which had started three months earlier. The pain intensity was rated as 5 out of 10 on the numeric rating scale (NRS; 0 = no pain, 10 = the worst imaginable pain). Her medical history was unremarkable, except for a right ankle inversion injury in December 2018. Gabapentin (Neurontin^®, Pfizer, Inc.) was initiated and titrated to 300 mg three times daily (tid), and duloxetine (Cymbalta^®, Lilly S.A.) was prescribed 30 mg twice daily (bid) at a community hospital to address suspected neuropathic and functional pain. Duloxetine was administered for approximately three months before the initial visit, with no reported side effects during this period. However, the patient reported no significant improvement in the pain.

The patient described persistent pain localized to the left medial malleolus and dorsum of the foot with no signs of allodynia or hyperalgesia. Physical examination revealed tenderness over the medial malleolus and redness around the lateral malleolus, but no temperature asymmetry in the lower extremities. No abnormalities in sweating, edema, motor function, or trophic changes were observed. Radiographs and a three-phase bone scan conducted outside hospital were unremarkable. However, infrared thermography indicated a 1.2°C temperature reduction in the left ankle compared to the right.

Fig. 1 summarizes the types and dosages of pain medications administered beginning in August 2019. Gabapentin was discontinued due to generalized edema, and duloxetine 30 mg bid was continued for suspected neuropathic pain. Tapentadol 50 mg (Nucynta ER^®, Janssen Korea Ltd.) bid was introduced, and subsequently increased to 100 mg bid during follow-up visits. The patient underwent lumbar sympathetic ganglion block procedures followed by radiofrequency thermoregulation. Despite adjustments in the medication regimen and procedures, her pain intensity remained above an NRS of 5. Consequently, in October 2019, oxycodone 5 mg (IRcodon^®, Unimed Pharm., Inc.) were prescribed as needed (pro re nata, PRN).

Fig. 1.

Types and dosages of pain management medications and severity of diaphoresis. The daily doses are expressed in milligrams (mg), except for Fentadur patch^® (μg/h). Periods without reported diaphoresis or when no records were available. P1: August 2019 ~ February 2020, P2: May 2021 ~ March 2022, P3: August 2024 ~ ongoing. Periods during which diaphoresis was reported. Yellow: reported diaphoresis; red, severe or increased diaphoresis. Upward-pointing red triangle (▲) indicates an increase in dose; downward-pointing blue triangle (▼) indicates a decrease in dose; superscript ‘c’ denotes the start of the drug. SA: serotonergic agent, ER: extended release, CR: controlled release, IR: immediate release, C: Cymbalta^®, L: Lyrica^®, N: Nucynta ER^®, T: Targin CR^®, O: Oxycontin CR^®, I: IRcodon^®, F: Fentadur patch^®.

Since February 2020, the patient had been taking oxycodone 5 mg up to tid. In March 2020, she first reported excessive sweating in her lower body. In April 2020, she was diagnosed with CRPS type I based on the Budapest criteria. The demand for pain medications gradually increased and, by August 2020, the dosage was adjusted to tapentadol 150 mg bid and oxycodone 5 mg up to five times daily. Around this time, due to a suspected mood disorder, the dose of duloxetine was doubled by the psychiatry department to 60 mg bid. In September 2020, she reported severe generalized sweating that significantly interfered with daily activities. In October 2020, tapentadol was replaced with oxycodone/naloxone 10/5 mg (Targin CR^®, Mundipharma Korea Ltd.) bid. Although there was a slight reduction in the severity of diaphoresis, the symptoms persisted.

In April 2021, due to aggravated fatigue, duloxetine was replaced with pregabalin 75 mg (Lyrica^®, Pfizer Inc.) bid. Following this adjustment, her fatigue improved and complaints of excessive sweating resolved. However, her depressive symptoms and generalized pain gradually worsened, accompanied by side effects such as weight gain and dry mouth.

Pregabalin was discontinued in March 2022, and duloxetine 30 mg bid was reintroduced. By that time, opioid dosages had been increased to oxycodone/naloxone 20/10 mg bid, oxycodone 5 mg four times daily, and fentanyl patch 12 μg/h (Fentadur patch^®, Lavipharm S.A.). One month later, the patient again reported severe generalized diaphoresis. Stellate ganglion near-infrared irradiation (SGR) was performed to alleviate diaphoresis; however, the relief was temporary.

In July 2022, oxycodone/naloxone was switched to oxycodone CR 10 mg (Oxycontin CR^®, Bard Pharmaceuticals Ltd.) tid, resulting in a slight reduction in sweating. However, as the oxycodone CR dose increased, sweating gradually worsened. In February 2023, due to refractory pain (NRS > 7), a spinal cord stimulator was implanted. Despite the implantation, reductions in pain medication were minimal, with no significant improvement in the severity of diaphoresis. In August 2023, clonidine was initiated at another hospital to manage diaphoresis, and the patient received periodic bilateral SGR treatments. However, the therapeutic effects were limited, and the patient required an indoor temperature of 20°C to manage symptoms. In July 2024, a second trial of replacing duloxetine with pregabalin 50 mg bid was conducted. One month later, during a follow-up visit, she reported complete resolution of diaphoresis and flushing, while her pain intensity remained unchanged. The second trial did not show any mood changes, weight gain, or dry mouth, and the patient remained under regular observation. Written informed consent was obtained from the patient.

DISCUSSION

Pharmacological treatment is a key modality for pain management, regardless of pain duration. While multimodal analgesia is emphasized for optimal pain control during Enhanced Recovery After Surgery, multidrug therapy for perioperative pain management remains important [4]. Similarly, multidrug analgesia is also commonly used for chronic neuropathic pain conditions such as CRPS, with SNRIs, TCAs, and anticonvulsants, whereas opioids remain controversial and may be considered for intractable cases [5,6].

In this case, the patient with CRPS had been taking various medications for an extended period owing to refractory pain. The serotonergic agents among her pain medications included duloxetine, tapentadol, oxycodone, and fentanyl patch. No other serotonergic agents were used in her treatment. Fig. 1 illustrates all pain medications and details regarding initiation, discontinuation, or dose adjustments over more than five years, offering novel insights into serotonin syndrome and its causative agents.

Serotonin syndrome is an iatrogenic disorder resulting from excessive activation of postsynaptic serotonin receptors due to medication use. The underlying pathophysiological mechanisms include: 1) increased synthesis, 2) decreased metabolism, 3) increased release, 4) receptor agonism, 5) increased receptor sensitivity, and 6) decreased reuptake [1-3]. Mechanisms particularly relevant to pain medications are increased release and decreased reuptake of serotonin [1,3]. Among medications used in pain management, SSRIs, SNRIs, and TCAs inhibit serotonin reuptake [1,3]. Certain opioids, including fentanyl, methadone, meperidine, and tramadol, also inhibit serotonin reuptake, while others such as oxycodone, buprenorphine, and tramadol enhance serotonin release [1,3,7].

The classic triad of clinical manifestations of serotonin syndrome includes neuromuscular hyperactivity, altered mental status, and autonomic hyperactivity, with a spectrum ranging from mild to life-threatening cases [8]. Mild cases are characterized by autonomic signs, such as tremors, mydriasis, and diaphoresis, typically without significant changes in vital signs. However, in moderate to severe cases, neuromuscular symptoms such as hyperreflexia and clonus may be observed, often accompanied by hemodynamic changes such as hypertension and hyperthermia, as well as altered mental status [2].

Serotonin syndrome is primarily a clinical diagnosis based on a comprehensive patient history and physical examination. A thorough patient history is essential to confirm the use of serotonergic agents and, if present, to assess the addition of new agents, dose escalation, or potential drug interactions [1-3,7,8]. The Hunter Serotonin Toxicity Criteria (Fig. 2) is the most accurate diagnostic tool, exhibiting high specificity in moderate to severe cases [1,8,9]. Clonus, characterized by rhythmic involuntary muscle contractions, is a key diagnostic feature within the Hunter Criteria and is particularly evident with ankle dorsiflexion [8]. However, mild serotonin syndrome can be difficult to diagnose, because it must be distinguished from underlying conditions and medication side effects, which complicate the application of the Hunter Serotonin Toxicity Criteria [1,8,9].

Fig. 2.

Hunter serotonin toxicity criteria. Adapted from the article of Dunkley et al. (Qjm 2003; 96: 635-42) [9] with original copyright holder's permission.

Before reviewing the serotonergic agents that the patient was taking, the critical aspect of diaphoresis must be evaluated. According to two retrospective studies involving patients diagnosed with serotonin syndrome, sweating symptoms were present in only 21% and 43% of patients, respectively [10,11]. Therefore, a definitive diagnosis of serotonin syndrome based solely on sweating symptoms was challenging, given the limited information available on neurological examinations, vital signs, and mental status in this case [8,9]. However, the concurrent use of two or more serotonergic agents, exacerbation of diaphoresis following the addition or dose escalation of opioids, and resolution of symptoms upon discontinuation of duloxetine strongly indicated that our patient likely developed serotonin syndrome (Fig. 1) [8].

The first case of diaphoresis was reported during an outpatient visit in March 2020. As shown in Fig. 1, there were periods in which the patient either did not report sweating symptoms or no related information was available: P1 from August 2019 to February 2020, P2 from May 2021 to March 2022, and P3 after August 2024. A common factor during P2 and P3 was the absence of duloxetine in the patient’s regimen. The absence of diaphoresis during P1 is less certain, as the assessment relied solely on outpatient records. However, significant diaphoresis appeared to begin following the escalation of tapentadol and oxycodone doses in February 2020. Following dose increases of the three medications, including duloxetine, diaphoresis became severe. The symptoms resolved after duloxetine was discontinued in April 2021, but recurred after the patient restarted duloxetine in March 2022. The symptoms continued thereafter, with varying severity depending on changes in the type and dose of opioids, until August 2024.

In summary, duloxetine was likely the primary causative agent, as the resolution of sweating symptoms during P2 and P3 strongly suggested this. The concomitant use of tapentadol, oxycodone and fentanyl patch was thought to have contributed to the worsening of symptoms through their respective mechanisms of action.

The suspected primary causative agent, duloxetine, has not been commonly associated with serotonin syndrome; however, case reports in which duloxetine alone induced this condition highlight the need for caution [12,13]. For instance, Choi et al. [12] reported a case of fibromyalgia accompanied by tremors, spontaneous clonus, and diaphoresis after 10 days of a single use of duloxetine 30 mg. The high selectivity of duloxetine for serotonin may explain its potential to induce the serotonin syndrome. Among the three common SNRIs, milnacipran inhibited the reuptake of serotonin and norepinephrine with equal affinity, whereas duloxetine exhibited 10-fold selectivity for serotonin, and venlafaxine exhibited 30-fold selectivity for serotonin [14].

Of the three opioids used by this patient, tapentadol inhibits the serotonin reuptake transporter, but is not associated with a higher incidence of this condition compared to other opioids [15]. Oxycodone can induce serotonin syndrome by directly acting on postsynaptic serotonin receptors or by increasing serotonin release, though the exact mechanism remains unclear [3,7]. Oxycodone has been reported to cause serotonin syndrome when combined with SSRIs or fentanyl [7]. Fentanyl, which inhibits serotonin reuptake [3], is one of the most common opioids associated with serotonin syndrome, as documented in World Health Organization's Global Database of Individual Case Safety Reports [7]. This prevalence may be attributed to the pharmacodynamics and frequent clinical use of fentanyl. Cases of serotonin syndrome associated with fentanyl patches have also been reported [3].

The cornerstone of serotonin syndrome treatment is immediate discontinuation of serotonergic agents. In mild cases, symptoms generally improve within 24 hours of the withdrawal of the causative agents. In moderate to severe cases, intensive monitoring and active conservative management are essential to prevent hyperthermia and multiorgan failure [1,2,8]. Benzodiazepine sedation should be considered when necessary. Additionally, antagonists such as cyproheptadine and chlorpromazine can be used [2].

Since serotonin syndrome is an iatrogenic condition caused by specific medications, preventive strategies are critical. Physicians should educate patients about potential side effects before prescribing serotonergic drugs, ensure appropriate medications, and minimize polypharmacy whenever possible [2]. When polypharmacy is unavoidable, a careful review of the patient’s medication list and assessment of potential drug interactions are essential. Case reports of serotonin syndrome indicate variable sensitivity to each serotonergic agent among individuals, possibly due to differences in drug metabolism or genetic polymorphisms that affect serotonin receptors [8]. Therefore, maintaining a high index of suspicion for serotonin syndrome is critical when managing patients on serotonergic medications.

As shown in Table 1, anesthesiologists and pain physicians frequently use pain medications that have the potential to induce serotonin syndrome during the perioperative period and in pain clinics. Depending on the patient’s comorbidities, psychiatric medications or antiemetics with the potential to trigger serotonin syndrome may also be necessary [1,6]. In conclusion, physicians who use pain medications are required to have a thorough understanding of serotonin syndrome and remain vigilant regarding the numerous medications that can precipitate it. Given the challenges in diagnosing serotonin syndrome, as highlighted in this case report, careful monitoring of changes in symptoms and signs following medication use is essential.

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