Dronabinol for the Treatment of Paraneoplastic Night Sweats in Cancer Patients: A Report of Five Cases

Introduction

Persistent sweating secondary to cancer and cancer therapies can substantially impact the quality of life for patients with an oncologic diagnosis. Hot flushes are vasomotor symptoms that present as periodic episodes of heat sensation. Often worse at night, they disrupt patients' sleep patterns, and they are frequently accompanied by palpitations and anxiety. These night sweats result in physical and emotional fatigue, depression, and reduced function, promoting a vicious cycle associated with the anorexia-cachexia syndrome that often afflicts cancer patients.^1–4

Hot flashes affect 50–85% of menopausal women, ⁵ with an incidence of 65–85% in breast cancer patients due to anti-estrogen therapies. ⁶ An association between night sweats and sleep disruptions, including awakenings for pain, has been reported in male patients. ² Studies indicate the prevalence of night sweats in the paraneoplastic population ranges from 10% to 48%,^1,7 presenting a major challenge in the symptomatic treatment of this group.

The exact mechanism for hot flushes is unknown. In general, sweating is stimulated when a hypothalamic response is triggered by fluctuations in core body temperatures, which can fluctuate nocturnally. ² An abrupt change in the levels of sex steroids can alter homeostatic regulation by the hypothalamus and has been proposed as a contributory mechanism.^1–3 This is particularly relevant in patients on hormonal therapies. Up to 80% of breast cancer survivors experience hot flushes, particularly if they are taking or have taken Tamoxifen or similar estrogen receptor antagonists for treatment. ⁸ Similarly, 34–80% of prostate cancer patients on androgen deprivation therapy report experiencing hot flushes. ⁹ Cancer cells release pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-1, and IL-6, all of which can contribute to flushing and sensation of heat and are associated with the anorexia-cachexia syndrome.^1,2 Regardless of etiology, these symptoms present a key problem in treatment of this population based on both their prevalence and disruption of quality of life. ¹

Various treatments have been proposed and studied to address night sweats. Traditional treatment options include both hormonal and non-hormonal pharmacotherapies, as well as integrative therapies such as cognitive-based therapy, yoga, acupuncture, and relaxation techniques.^4,10–13 Selective serotonin reuptake inhibitors (SSRIs), α-adrenergic agonists, β-blockers, antidopaminergic agents, aromatase inhibitors, vitamin E, gabapentin, progesterone, thalidomide, black cohosh, and soy phytoestrogens have all been proposed but are generally not used due to lack of efficacy or side effects.^3,7,14–19

Cannabinoids are commonly used for treatment of nausea, neuropathic pain, and anorexia in cancer patients. ²⁰ Some studies support the use of nabilone, a synthetic analogue of 9-tetrahydroxycannabinol (9-THC), in the treatment of night sweats in cancer patients as well. ¹ Nabilone is an agonist at CB1 and CB2 receptors that has been used outside the United States for the treatment of hot flushes in cancer patients. Cannabinoids have been shown to modulate cytokine activity as well as produce hypothermia in mouse models, and it is possible that nabilone is effective in mitigating night sweats by these methods. ¹ However, since nabilone is unavailable in the United States, dronabinol should be investigated as a potential candidate for palliation of night sweats because it is available and works by a similar mechanism. The following describes case reports of five patients with metastatic disease who were suffering from paraneoplastic night sweats and whose symptoms were subjectively palliated with dronabinol.

Method/Case Descriptions

A retrospective search of past medical records identified a convenience sample of five patients with oncologic disease who complained of night sweats that meaningfully interfered with their quality of life and were resistant to traditional therapies. All patients had established care with the outpatient consultative palliative medicine program at Stanford Medical Center; they agreed to try “off label” oral dronabinol for palliation of their night sweats between 2013 and 2016 and subjectively reported on its efficacy. Each patient had a comprehensive evaluation by the palliative care team for symptom management and quality of life issues. Patients were excluded if determined to be medically incompetent to make decisions regarding their care.

Patients were asked to describe their symptoms in qualitative terms at the initial visit and at each subsequent outpatient visit. Edmonton Symptom Assessment System (ESAS) questionnaires are generally obtained from all patients to determine severity of symptoms such as pain, nausea, shortness of breath, fatigue, and anxiety. Although ESAS evaluates well-being, it does not specifically address night sweats, and therefore, it was not used to evaluate the specific case reports on these patients with night sweats. The patients' verbal statements were used as evaluation of the therapy.

Patients ranged in age from 29 to 72 years (Table 1). Two patients were female and three were male. Two were diagnosed with Acute Myeloblastic Leukemia and the others with colon cancer, rectal cancer, and breast cancer. Patients were at different stages in their disease-modifying therapies. All participants underwent a thorough evaluation by the palliative care team and were medically stable at time of treatment. None of the patients were found to be febrile or have acute symptoms of infection. Medication review did not suggest any known cause of night sweats. All patients had reported night sweats as a major cause of distress for several weeks. Patients were re-evaluated in clinic monthly, but phone follow-up was obtained after the first week to evaluate efficacy of the medication.

Three patients were given 5 mg at bedtime (HS) and one was started at 5 mg TID and subsequently titrated up to 10 mg TID due to increased symptoms (Table 2). One elderly patient was started at 2.5 mg BID. Patients were evaluated on the next scheduled visit one to four weeks after therapy was initiated. After three days of initiating therapy, one patient reported a change in the severity of night sweats. Two patients reported a complete resolution of night sweats. The other three patients reported a decrease in the severity of their night sweats, resulting in them only having to change clothes once or not at all in the night. One patient decided to stop the dronabinol due to sedation and reported that his night sweats returned when it was discontinued.

Discussion

Although there is limited evidence for use of dronabinol in the treatment of night sweats, it was subjectively successful in palliating this symptom in a limited number of patients with oncologic disease. The five patients we examined originally described their night sweats as greatly interfering with their sleep, which negatively impacted their daytime quality of life as well. Once the patients experienced resolution of their night sweats, other symptoms such as anxiety and fatigue improved as well, which lead to an improvement of their overall quality of life. Symptoms resolved in less than one week of initiating the dronabinol for all five patients.

Our study was limited by its retrospective nature and small sample size. Future research could benefit from a double-blinded randomized trial of dronabinol versus placebo treatment for the management of night sweats in patients with oncologic disease. The development of standardized forms to better objectify patients' responses to dronabinol and to evaluate for night flush management would be beneficial as well. Medical cannabis is legal in multiple states and continued research into its potential therapeutic value is necessary.