Reprinted with the kind permission of Cort Johnson  and Health Rising.
Doctors and patients are increasingly being warned to avoid opioid painkillers if possible, but an important factor in the opioid painkiller issue is often missed. Benzodiazepine drugs, including some like Klonopin, that are often used in FM and ME/CFS, when taken with some opioid painkillers, can significantly increase the risk of dangerous side-effects.
The dangers opioid painkillers pose to those who abuse them or improperly use them are well known. Deaths from opioid painkillers, for instance, have increased four-fold in the past 15 years and the FDA has produced stern warnings about their misuse.
Opioid painkillers aren't the only drugs, though, that play a role in opioid issues. A recent study suggests that benzodiazepine drugs that are commonly used in the fibromyalgia and chronic fatigue syndrome communities such as klonopin (clonazepam) play a significant role in deaths associated with opioid painkillers.
Benzodiazepines pose a risk to those using opioid painkillers because their similar sedating effects can potentiate the problem of "respiratory depression." Respiratory depression occurs when a central nervous system inhibiting drug depresses breathing activity. A victim of respiration depression simply goes to sleep and doesn't wake up. It's a common way to die from opioid painkiller misuse.
Studies suggest that nearly 30% of deaths associated with opioid painkillers involve benzodiazepines. The CDC recently warned physicians about the dangers of combining both classes of drugs, and the FDA requires "black box" warnings be put on the drug labels, but some evidence suggests that concurrent use of these two drugs is still common. Nearly 30% of veterans prescribed opioids at a Veterans Administration hospital, for instance, were also taking benzodiazepines.
The actor Heath Ledger  died from using a mixture of prescription opioid and benzodiazepine drugs.
Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis. Eric C Sun, Anjali Dixit, Keith Humphreys, Beth D Darnall, Laurence C Baker, Sean Mackey. BMJ 2017;356:j760 http://dx.doi.org/10.1136/bmj.j760 
Essentially the study asked if benzodiazepine use in people taking opioid painkillers was increasing over time, and if it was, what effects it was having. It examined trends in benzodiazepine/opioid use over more than a decade to see: a) how many people were using both; b) if benzodiazepines were being prescribed more frequently than before; and c) it determined what impact combining those two drugs had on the incidence of opioid overdose emergency room visits over the past 13 years. This large study combed through the records of almost 600,000 patients to identify over 300,000 patients who at some time had had an opioid painkiller prescription filled.
Opioids: fentanyl (patch or oral form), hydrocodone, hydromorphone (oral form), methadone, morphine, oxymorphone, oxycodone. (Note: Tramadol not assessed)
Benzodiazepines: alprazolam (Xanax), chlordiazepoxide, clonazepam (Klonopin), clorazepate, diazepam (Valium), estazolam (ProSom), flurazepam, halazepam, lorazepam (Ativan), midazolam, oxazepam, prazepam, quazepam, temazepam, triazolam.
The study found that the percentage of patients using both benzodiazepines and opioids almost doubled (9 – 17%) over 13 years. Most of the increase came from intermittent users of opioids; those who used opioids once or from time to time but did not use them chronically.
The percentage of opioid painkiller users visiting the emergency room or who became hospitalized because of issues with their painkillers rose by about thirty percent from 2001 to 2013. Overall, the risk was relatively low: about 1% of those using opioid pain-killers visited the emergency room or became hospitalized in 2001 and 1.35% of those did in 2013.
Chronic opioid users exhibited a much higher rate of emergency room visitation/hospitalization than intermittent users (chronic – 3.5%; intermittent – 1.15%).
Using benzodiazepines in combination with opioids almost tripled one's chances of landing in the emergency room or being hospitalized (@4% for the entire population). That risk zoomed up to 5.6% for chronic opioid users. Intermittent opioid users who also used benzodiazepines were at much less risk (1.5% in 2013), but using benzodiazepines increased their odds of visiting the emergency room by about 50%.
Overall, the study found that not using benzodiazepines in conjunction with opioids would reduce emergency room visits/hospitalizations because of opioid painkillers by about 15%. Because it did not include people who visited the emergency room and then died from the opioid-painkiller abuse, it underestimated the true risk of using these two drugs together.
Tramadol Not Assessed
Because Tramadol – a weaker opioid often used in fibromyalgia – was not included in the survey, it's impossible to assess the effects concurrent benzodiazepines have on it. Tramadol is a weaker opioid drug that poses less risk of abuse and misuse than other opioid drugs. The FDA included Tramadol in the list of opioid drugs in its Safety Announcement  regarding benzodiazepines and opioids.
According to several sites, however, Tramadol is considered to pose a smaller risk of respiratory depression than other opioid drugs. cause respiratory depression although the risks appear to be quite low, and eMeD Expert  states that:
"Respiratory depression with tramadol is less pronounced, and occurs less often, in comparison to equianalgesic doses of morphine. In large clinical and post-marketing studies including over 21,000 patients, no clinically relevant respiratory depression was reported. However, respiratory depression can occur, in particular with overdose or with impaired renal function."
From the FDA's Safety Announcement :
"Patients taking opioids with benzodiazepines, other CNS depressant medicines, or alcohol, and caregivers of these patients, should seek medical attention immediately if they or someone they are caring for experiences symptoms of unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness. Unresponsiveness means that the person doesn’t answer or react normally or you can’t wake them up."
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Benzodiazepines taken in combination with most opioid painkillers substantially increase the risk patients might need to visit an emergency room or be hospitalized due to the effects of opioids.
Intermittent opioid users appear to be at much lower risk of landing in an emergency room or becoming hospitalized because of benzodiazepine / opioid associated problems than chronic opioid users (intermittent users – 1.5%; chronic users – 5.6%).
Because the study did not assess people who visited the emergency room or who were hospitalized and later died, it probably underestimated the risks of concurrent drug use. The study also did not assess the effects of dose – presumably an important factor in respiratory depression.
Because the effects of Tramadol – perhaps the most frequently used opioid painkiller in fibromyalgia and ME/CFS – were not assessed, it's impossible to determine the effects of benzodiazepines on it. The FDA included Tramadol in its Safety Warning. Several other websites, however, state that Tramadol poses a considerably lower risk of respiratory depression than other opioids.
About the Author: ProHealth is pleased to share information from Cort Johnson. Cort has had myalgic encephalomyelitis /chronic fatigue syndrome for over 30 years. The founder of Phoenix Rising and Health Rising, he has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort's and other bloggers' work at Health Rising .