Opioids Causing Peripheral Edema
Jacqueline Gardner-Nix, MB BS, PhD, MRCP(UK) Open AccessDOI:
https://doi.org/10.1016/S0885-3924(02)00404-9
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To the Editors:
Opioid analgesics have rarely been reported in the literature to cause peripheral edema when administered orally.1 However, peripheral edema is often seen in late stages of cancer and is usually treated conservatively. We describe five cases of non-cancer pain treated with opioids, which highlight their ability to cause peripheral edema. The non-cancer pain patients described were referred for treatment with opioids after other avenues of pain relief had been explored and failed.
Case 1
At the time of referral, A 67-year-old woman was receiving 60 mg of slow-release morphine every 12 hours for chronic pain associated with a pronounced kyphoscoliosis, osteoporosis, sciatica, a fractured thoracic vertebra after a motor vehicle accident many years before, and a cervical fusion. Other medications included digoxin 0.25 mg daily, verapamil 240 mg daily to control atrial fibrillation, enteric-coated aspirin 325 mg daily, thyroxine 0.075 mg daily, conjugated estrogens 0.625 mg daily, progesterone 2.5 mg daily, and prednisone 5 mg three times weekly for polymyalgia rheumatica. As pain control was suboptimal, her morphine was increased to 90 mg every 12 hours and 10 to 20 mg of short-acting morphine was allowed every 4 hours as needed. The increase caused sedation and nausea, and she was switched to transdermal fentanyl 50 μg per hour (patch changed every three days), with initial improved pain relief, less sedation, and no nausea. She required an increased dose after a couple of weeks, and was titrated gradually to 100 μg per hour. This increase was followed by the onset of pitting pedal edema to the mid-calf bilaterally. She returned to the slow-release morphine, with resolution of the edema within 48 hours.
Case 2
A 57-year-old woman was referred with chronic low back pain following surgery to her cervical and lumbosacral spine many years before. Despite many pain management interventions, she had become virtually wheelchair-bound because of the pain. At presentation, she was taking slow-release oxycodone 320 mg every 6 hours, transdermal fentanyl 200 μg per hour (patch changed every two days), and prochlorperazine 10 mg every 6 hours as needed for nausea. Pain intensity ranged between 7 and 10 on a 0–10 scale (0 = no pain, 10 = excruciating pain). She was quite somnolent during the day but complained of insomnia. She reported that doses in excess of 200 μg per hour of the transdermal fentanyl caused peripheral edema. She was titrated down on her opioids as methadone 5 mg every 6 hours was started. The dose was gradually increased over the next few weeks as the other opioids were discontinued. When her methadone was titrated beyond 480 mg per day, she reported extensive pitting edema up to her thighs, and also in her arms and hands. The methadone was cut back to 150 mg per day, and supplemented with slow-release oxycodone 360 mg daily. The peripheral edema resolved in 48 hours.
Case 3
A 42-year-old woman was referred to the pain clinic with severe low back pain secondary to episodes of trauma when lifting heavy objects in the factory. She had undergone three back surgeries and had also had implantation of a spinal cord stimulator, which was no longer effective. She had a neurogenic bladder and was practicing self-catheterization. She was taking acetaminophen/codeine (30 mg) tablets up to 6 daily as needed, and hormone replacement. She walked with the aid of a cane and exhibited significant tremor and spasm in both legs. She was started on transdermal fentanyl 25 μg per hour (patch changed every three days), with immediate improvement of her pain, but she reported edema of both ankles and hands within 24 hours. She was switched to slow-release oxycodone, initially at 10 mg every 8 hours, but the edema continued. Pain relief was inferior on the second regimen and she requested resumption of transdermal fentanyl, and treatment of the edema with a diuretic. Furosemide 20 mg daily was started, which reduced but did not eliminate the edema. Two months later, she was taking 50 μg per hour of transdermal fentanyl and reported improvement in the edema. She was using the furosemide only as needed.
Case 4
A 72-year-old man suffered chronic neck and upper back pain since a fractured C5 vertebra from trauma many years prior. He had undergone two anterior fusions followed by a posterior fusion. He was consuming acetaminophen/codeine (30 mg) tablets up to 20 daily. He was given slow-release morphine, and titrated to 400 mg every 8 hours, with excellent pain control. This treatment was associated with painful bilateral pitting edema up to the thighs. He was switched to slow-release oxycodone, titrated to 80 mg three times daily, and experienced good pain relief with resolution of the edema. When his dose was increased to 120 mg three times daily for pain exacerbation, he developed pitting edema, which was exacerbated by air travel. The edema resolved when his dose was reduced below 80 mg every 8 hours. He was subsequently treated with furosemide and spironolactone, so that his dose of slow-release oxycodone could be maintained around 100 mg every 8 hours for improved pain management.
Case 5
A 40-year-old man presented with a several year history of low back pain caused by a work injury. He had undergone three back fusions. Ambulation was limited, and he used a scooter to get around outside the home. He had a neurogenic bladder. At presentation, he was taking slow-release morphine 120 mg every 12 hours, short-acting morphine 10 mg up to 4 times daily for “rescue,” and amitriptyline 150 mg at night. Pain relief was suboptimal, and he was started on gabapentin 300 mg daily. The dose of gabapentin was increased. Later, the slow-release morphine was increased to every 8 hours, with 25 mg of short-acting morphine up to three times daily for rescue. He had slight pitting edema of his ankles at presentation, and over the next few weeks edema ascended to his waist. Gabapentin was discontinued, as it had not proved beneficial for his pain, and was thought to be causing the edema. Meanwhile the slow-release morphine was titrated to 300 mg every 12 hours. He was subsequently switched to slow-release oxycodone, which was titrated to 240 mg every 12 hours, but edema continued to be a problem. Furosemide 80 mg daily did not control the edema. He was admitted to hospital for diuresis, with good results, but as intravenous diuretics were switched to oral, edema started to re-accumulate. He was switched from slow-release oxycodone to transdermal fentanyl, titrated to 300 μg per hour(patch changed every two days), and the edema gradually resolved. He has been on the same dose of transdermal fentanyl with good pain control and no requirement for diuretics for the last 15 months.
Comment
These cases illustrate the potential for opioids to cause peripheral edema, reversible on withdrawal or change of opioid, but sometimes reversible spontaneously if edema is minor. It would be advisable to consider the opioid in a palliative patient with cancer who becomes edematous shortly after starting a new opioid. It is also important not to miss it in a non-cancer pain patient, where a switch to another opioid could be beneficial. Opioids are well known to cause smooth muscle relaxation in the gut, produce hypotension, reverse peripheral edema, and are known to be involved in histamine release.2, 3 Their mechanism of action is unclear in the etiology of peripheral edema. Further studies are indicated to assess the incidence and etiology of edema in patients treated with opioids.
