[Pain - You Only Live Twice (2011)
Iberio Ralda
Pain caused by cancer that has spread, or metastasized, to the spine is a major problem for many patients. New findings from a clinical trial indicate that, for some patients with painful spinal metastases from advanced cancer, a type of precise, high-dose radiation therapy may be a highly effective way to relieve that pain.
About a third of people in the clinical trial who received this form of radiation therapy, called stereotactic body radiation therapy, or SBRT, for spinal metastases were pain-free up to 6 months after treatment, compared with only about 15% of people who received conventional external beam radiation therapy to treat the pain.
In recent years, because it can more precisely target tumors, SBRT has come to be widely used for people with only a few, small metastatic tumors (known as oligometastatic cancer), including those in the spine, he added. Some studies have shown that if these few metastases can be successfully treated, patients may live for years or decades.
Because of their potentially good prognosis, people with oligometastatic cancer were thought to be more likely than people with advanced metastatic disease to benefit from SBRT, which is more expensive and has a higher risk of causing some types of damage in the spine than conventional radiation therapy, Dr. Sahgal explained.
But the limitations of conventional radiation therapy as a palliative treatment for people with advanced cancer and spinal metastases eventually led researchers to wonder if SBRT might also be a better option for people with limited life expectancy.
The new trial was conducted by the Canadian Cancer Trials Group, part of NCI's National Clinical Trials Network. It included about 200 people who had three or fewer spinal metastases in a concentrated area of the spine that were the sole source of their pain. None had measurable signs of instability in the bones of the spine, which would increase the risk of fracture and make it harder to assess pain.
Measurements of spinal stability after 6 months were about the same in both groups. The risk of compression fractures was also similar in both groups, and the risk of serious fractures was minimal, the researchers reported. There were also no reports of damage to the spinal cord caused by the radiation treatments.
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Background: Vital statistics data suggest that the opioid pain reliever (OPR) methadone is involved in one third of OPR-related overdose deaths, but it accounts for only a few percent of OPR prescriptions.
Results: Methadone overdose deaths and sales rates in the United States peaked in 2007. In 2010, methadone accounted for between 4.5% and 18.5% of the opioids distributed by state. Methadone was involved in 31.4% of OPR deaths in the 13 states. It accounted for 39.8% of single-drug OPR deaths. The overdose death rate for methadone was significantly greater than that for other OPR for multidrug and single-drug deaths.
Implications for Public Health Practice: Health-care providers who choose to prescribe methadone should have substantial experience with its use and follow consensus guidelines for appropriate opioid prescribing. Providers should use methadone as an analgesic only for conditions where benefit outweighs risk to patients and society. Methadone and other extended-release opioids should not be used for mild pain, acute pain, "breakthrough" pain, or on an as-needed basis. For chronic noncancer pain, methadone should not be considered a drug of first choice by prescribers or insurers.
Recent analyses have shown that methadone was involved in one in three opioid-related deaths in 2008 (7). Moreover, the involvement of methadone in drug overdose deaths, in toxic exposures quantified by poison centers, and in diversion to nonpatients is disproportionate to the number of methadone prescriptions for pain when compared with other opioid pain relievers (3,8). Analysis of ED data indicates that the estimated number of ED visits resulting from nonmedical use of methadone alone or in combination with other drugs in 2009 (n = 63,031) was significantly greater than the estimated number in 2004 (n = 36,806) (4). CDC reviewed national data on trends in methadone use and mortality and data from medical examiners on methadone mortality to determine whether additional recommendations for its safe use for pain treatment are necessary.
Comparison of methadone to other major opioids in DAWN data was based on rates of death per 100 kg of opioid analgesic in MME. Drug-specific rates were compared using rate ratios and 95% confidence intervals with the rates for methadone as the referents.
The rate of overdose deaths involving methadone in the United States in 2009 was 5.5 times the rate in 1999 (Figure 1). The mortality rate peaked at 1.8 deaths per 100,000 persons in 2007 and then declined in parallel with the amount of methadone being distributed nationally in 2008 and 2009. The annual rate of methadone prescriptions for pain rose to 1.5 per 100 persons by 2008 and did not increase further in 2009. Methadone accounted for 4.4 million (1.7%) of the 257 million opioid prescriptions in 2009. However, in 2010, methadone accounted for 9.0% of all the MME of all major opioids tracked by ARCOS other than buprenorphine. This proportion varied by state from 4.5% in New Jersey to 18.5% in Washington (Figure 2).
Among the 13 DAWN Medical Examiner states, methadone accounted for 9.8% of the MME tracked by ARCOS. Methadone was involved in 31.4% of the 3,294 deaths involving these opioids, more than any opioid other than oxycodone in 2009 (Table). Among the 748 single-drug deaths, methadone was involved in 298 (39.8%), twice as many as any other opioid. The rate of methadone deaths per 100 kg sold in MME was significantly higher than that for any other opioid for both all deaths and single-drug deaths. The difference between methadone and other opioids was more pronounced in the analysis of single-drug deaths. Even if some of these deaths (e.g., 25%) had been attributable to methadone dispensed from opioid treatment programs, the differences between methadone and other opioids would remain significant. The methadone death rate was still significantly higher than the rate for any other opioid in both comparisons.
The primary advantages of using methadone over other opioids for pain treatment are its long duration of action, relatively low cost, and availability in liquid formulation for oral use. Its primary disadvantages are its long and unpredictable half-life and associated risk for accumulating toxic levels leading to severe respiratory depression; its multiple interactions with other drugs, including frequently abused drugs such as antianxiety agents; and its ability to cause major disturbances of cardiac rhythm (12).
Increased use of methadone since 1999 might have been prompted by growing costs of treating pain with opioids and increasing reports of abuse of other, more expensive, extended-release opioids (1). Overdose reports and interventions by FDA and DEA might have resulted in declines in the amount of methadone distributed and methadone-related fatal overdoses in 2008, although the number of methadone prescriptions did not decline. The parallel trends in the amount of methadone distributed for use as a pain reliever and in the methadone mortality rate are consistent with methadone prescribed as a pain reliever being the primary determinant of methadone mortality rates (1,3).
Data suggest that some of the current uses of methadone for pain might be inappropriate. According to an analysis conducted by FDA, the most common diagnoses associated with methadone use for pain in 2009 were musculoskeletal problems (such as back pain and arthritis) (46%), headaches (17%), cancer (11%), and trauma (5%). Most methadone prescriptions were written by primary care providers or mid-level practitioners (e.g., nurse practitioners) rather than pain specialists. Nearly a third of prescriptions appear to have been dispensed to patients with no opioid prescriptions in the previous month (i.e., opioid-nave patients) (10).
The findings in this report are subject to at least five limitations. First, vital statistics underestimate the number of overdose deaths from specific drugs because the type of drug is not specified on many death certificates. Second, medical examiners in the DAWN system might have varying definitions of drug-related deaths. However, individual medical examiners likely apply the same definitions to all types of opioid analgesics. Third, assigning responsibility to any single drug in multidrug overdoses is difficult. However, this is not an issue in single-drug deaths, among which the highest risks for methadone were observed. Fourth, some deaths might have resulted from methadone provided in take-home doses by opioid treatment programs, but adjusting for such deaths in this analysis did not change the overall results. Finally, ARCOS data reflect distributions to retail outlets by state, but some drugs might have been used by residents of neighboring states.
This study and others suggest that methadone remains a drug that contributes disproportionately to opioid pain reliever overdoses and associated medical and societal costs. Additional warnings to prescribers about dosage are likely to have limited effect, given the high prevalence of use without a prescription among persons who overdose. The public health goal now should be to mount a concerted effort to reserve methadone for those pain-related conditions for which the benefits likely outweigh the risks to patients and society, such as use for cancer-related pain or palliative care. This will reduce the amount of methadone available for diversion and nonmedical use.
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