Physicians treating advanced cancer patients with intractable pain may want to consider adding methadone to opioids, according to Sydney Morss Dy, MD, MSc.
Dr. Dy, associate professor and physician leader of the Duffey Pain and Palliative Care Program at Hopkins Kimmel Cancer Center in Baltimore, spoke about this and other key challenges in pain management for cancer patients at the American Society of Clinical Oncology's annual meeting, held in Chicago this past spring.
Using methadone as an adjuvant to opioid therapy in advanced cancer patients with moderate to severe cancer pain “is something that we've been doing a little bit in our practice and had some good success with,” she said. She stressed that physicians should proceed with caution and ideally with the input of a practitioner who has experience prescribing methadone.
A 20-patient retrospective case series, published in the Journal of Palliative Medicine in 2013, examined patients who began receiving methadone as an adjuvant to opioids rather than converting to methadone alone. Forty percent had a decreased pain score of two points or more after one month, with no increase in adverse effects, Dr. Dy said.
“This is actually a pretty good finding,” she noted. “It's often very hard to see that kind of difference in a pain study.”
She also pointed out that although patients in the study were taking very high doses of morphine, their methadone doses were low, a total of 15 mg/d. “In patients with advanced disease on a lot of opiates, sometimes this is a good option to kind of give them some extra time before they need that PCA [patient-controlled analgesia] or to do something a little different that's going to get them some pain relief for a few months,” she said.
Risk assessment for opioid abuse is important in cancer patients as in other patient populations, and Dr. Dy recommended following guidelines from the American Pain Society, the American Academy of Pain Management, and the American Society of Interventional Pain Physicians that were published in Pain Physician in 2012. They state that physicians should do the following:
- Document psychiatric status, substance abuse history and screening for past opioid use.
- Perform a detailed pain and opioid risk assessment.
- Prescribe opioids judiciously.
- Monitor prescriptions and use.
- Set pain management goals.
“It's really important to try and really think about the patient and think about whether opiates are the best treatment and whether there are other options before starting opiates,” Dr. Dy said.
Dr. Dy also discussed adjuvant therapy for chemotherapy-induced peripheral neuropathy and pegfilgrastim-induced pain.
“Chemotherapy-induced peripheral neuropathy, as many of you know, is a very challenging situation. Many patients will tell you they've tried lots of things and nothing helps, and it really affects their quality of life in many ways,” she said.
Evidence in this area is limited and large trials are lacking, Dr. Dy said, so clinicians often find themselves translating evidence from trials in diabetic patients or patients with general cancer neuropathy to this population.
A randomized clinical trial of about 200 patients, published in the Journal of the American Medical Association in 2013, did indicate that duloxetine therapy could be helpful for neuropathy related to chemotherapy, but Dr. Dy pointed out that the difference between the treatment and placebo arms was only 0.73 on a 10-point scale, with 20% more patients in the treated group reporting decreased pain. She also stressed that a significant number of patients dropped out after the initial treatment period and that the between-group difference was seen only during the crossover period.
The study results mirror what Dr. Dy has seen in her practice. “We've been trying to use duloxetine more, especially since this study came out. We've used this in a number of patients and we haven't had very good success with it,” she said. “Many of our patients have a lot of difficulty with this medication, and even our patients who have been able to tolerate it haven't really reported that it has helped.”
Pegfilgrastim-induced pain is also common in patients with cancer, Dr. Dy said, and a 2012 study published in the Journal of Clinical Oncology found that naproxen might help, with a difference of one point on a 10-point pain scale.
“I think there's a lot more interest, now that we know a lot more about the difficulties with opiates, in thinking more about going back to [acetaminophen] and [nonsteroidal anti-inflammatory drugs] and looking at those medications in cancer patients,” Dr. Dy said.
For patients with bone pain due to metastases, a single fraction of palliative radiotherapy is optimal, Dr. Dy said. She and her colleagues reviewed four systematic reviews and 13 randomized, controlled trials and found no significant difference in pain between patients who received one fraction of radiation therapy for bone metastases and those who received more.
However, in the U.S., more extensive treatment is often recommended despite best evidence. This wastes resources and can also do patients more harm than good, Dr. Dy said. She mentioned one of her patients who had new rib pain due to metastatic disease but had reportedly refused radiation treatment. When Dr. Dy asked why, the patient said he was told that he had to come in for 10 fractions.
“This is a patient with really debilitating fatigue, and he lives an hour and a half away,” Dr. Dy said. “So for him there was no way that he could tolerate or that it was worth it for him to come for those 10 fractions of radiation, and that's the only option he was offered.”
Dr. Dy pointed out that the American Academy of Hospice and Palliative Care chose limiting more extensive radiotherapy for painful bone metastases as one of its recommendations in the American Board of Internal Medicine Foundation's Choosing Wisely campaign. In addition, the American Society of Radiation Oncology's 2011 guidelines recommend one fraction of radiotherapy for patients with limited life expectancy.
Dr. Dy also reviewed the research on vertebroplasty/kyphoplasty for vertebral compression fractures. Two randomized, controlled trials published in the New England Journal of Medicine that compared vertebroplasty/kyphoplasty with sham procedures found no benefit in noncancer patients. Subsequent studies in noncancer patients did show benefit for pain management but did not use a sham procedure, which Dr. Dy said is a big issue in pain studies because of placebo effects.
In addition, she said, some of the favorable studies have involved patients who had been in pain for a longer period, and with compression fractures and with pain syndromes in general, people tend to improve over time. “If you only take the patients who already haven't improved over several months, you're probably looking at a more resistant population that's probably going to be more likely to benefit from the procedure,” she said.
However, Dr. Dy noted that a 2011 randomized, controlled trial of kyphoplasty in patients with cancer published in Lancet Oncology found a significant decrease in back-related disability at one month. The trial had some important caveats—for example, it did not use blinding or a sham procedure and was done in a very selected population—but Dr. Dy said it indicates that the procedure could be helpful for some patients.
“For someone particularly who can't tolerate opiates or really just has a single bone metastasis compression fracture, a single source of pain, it's a nice option,” she said.
Physicians caring for cancer patients should remember that nonmedical options can sometimes be just as effective as medications and procedures and that education is a very important part of pain management, Dr. Dy said. In a 2013 analysis of 17 studies, which was published in the American Journal of Hospice and Palliative Care Medicine, seven studies (41%) found that patient education through multimodal contacts, such as in-person visits and videos, had a statistically significant impact on pain.
Quality measurement is also an evolving area. “There's some evidence that quality measures and quality improvement can make a difference in pain management,” she said. A study published in the American Journal of Managed Care in 2011 compared sites that had just joined the American Society of Clinical Oncology's Quality Oncology Performance Initiative with those that had been participating for a longer period. The authors found that the new sites performed worse on quality measures for pain management, such as having a plan in place to manage pain and assessing pain before death, than established sites.
“I think this is some potential evidence that being aware of pain management in our practice and what some potential issues are and then addressing those issues can make a difference for our patients,” Dr. Dy said.
For opioid-induced constipation, another huge issue in cancer patients with pain, Dr. Dy recommended considering the option of polyethylene glycol. A 2010 Cochrane meta-analysis of 10 randomized, controlled trials found that it performed better than lactulose, leading to more stools and less abdominal pain.
“We are using a lot of this medication in our practice over the last few years and often find that it's pretty well tolerated by patients, with good education that goes along with it, because it often doesn't work the way patients think it's going to,” she said. It can take a day or two before it starts working, so it is better as a maintenance medication than for acute constipation, she noted.
Dr. Dy also mentioned the injectable subcutaneous medication methylnaltrexone, which reverses the effects of opiates in the gastrointestinal tract. A 2011 Cochrane review of three randomized controlled trials comparing this treatment in palliative care settings with placebo found an odds ratio of 6.95 for laxation at four hours, with very low rates of serious adverse events.
“It's something to use rarely, but another good option that we have for the patient who's really struggling or really is having a bad time and hasn't been able to get their opioid-induced constipation under control,” Dr. Dy said.
Dr. Dy noted that most physicians treating opioid-induced constipation give docusate and senna together, but she said doing so might not be necessary. A randomized, controlled trial published in the Journal of Pain and Symptom Management in 2012 found that adding docusate to senna in 74 hospice patients led to no difference in stool frequency or volume.
The original reason for adding docusate to senna was to reduce cramping, not to soften stool, and in some cases it can actually make things worse by softening the stool too much, Dr. Dy said. Instead of giving docusate automatically along with senna, physicians should use it more judiciously and consider each case individually, she recommended.
“We shouldn't necessarily give everybody docusate just because they're taking senna,” she said.