In recent years, an avalanche of evidence has been published against the use of opioid and non-steroidal anti-inflammatory drugs (NSAIDs) in medical journals, which has led many physicians to reevaluate the risk-benefit ratio of these drugs. Almost all publications in the last 5 years have reported negative results or have highlighted additional risks.
With such a clear focus on the negative aspects of these drugs, some providers have begun to raise several areas of concern. They question the place of medications in therapy; They wonder how to use them properly; And-perhaps most importantly-they are asking what safe analgesic therapies are left for their patients. Unfortunately, disinformation is ubiquitous, and this generalized uncertainty has resulted in greater difficulty in interpreting new evidence and in deciding optimal pain management regimens.
This comment provides clarity on 10 myths of analgesics selected by the authors.
Myth Number 1:
NSAIDs are more dangerous than opiates
Comparisons between NSAIDs and opiates are complicated by a large number of confounding factors, such as estimates of population use, the absence of direct comparisons in randomized trials, and the general hysteria surrounding both classes of drugs. The lack of high quality evidence, however, prevented many (physicians and patients) from assuming that the toxicity of NSAIDs is greater than that of opioids. The results of two national surveys of the Centers for Disease Control and Prevention (CDC), the National Health Interview Survey (NHIS) and the National Health and Nutrition Examination Survey (NHANES) are useful for a comparison.
As a background, in April 2005, the Food and Drug Administration (FDA) issued a box warning that will be included on the labeling of all NSAIDs, stating: NSAIDs are associated with increased risk of cardiovascular thrombotic events infarction and stroke; And NSAIDs can increase the risk of irritation, inflammation, ulceration, bleeding, and gastrointestinal (GI) perforation. These events can occur at any time during treatment and without notice. In July 2015, FDA strengthened warnings of cardiovascular events (CVs) with NSAIDs as a class effect, increasing providers’ reluctance to use these medications.
In 2010, 12.8% of the population regularly took prescription and over-the-counter (OTC) NSAIDs regularly. This compares with 6.8% of the population receiving prescribed opiates.5 The number of deaths attributed Year to gastrointestinal bleeding was 7,215 That less than half are typically attributable to the use of NSAIDs.6 This number is often compared with data on opioid overdose -15,597 deaths in 2009.
In fact, only one study directly compared toxicity between the two classes of medication in a population that was predominantly older women (mean age 80 years). Because studies have shown that the elderly (> 65) are 2 to 3 times greater risk of gastrointestinal bleeding compared to younger patients, the survey should have reflected a higher toxicity of NSAIDs. However, compared to NSAIDs, opioids had a mortality risk ratio For all causes of 1.87, with an increased risk of hospitalization for adverse events, fractures, cardiovascular events and bowel obstruction, all of which increased compared to NSAIDs.
A number of additional factors contribute to the toxicity of NSAIDs and more bias data. Sixteen percent of the population uses NSAIDs and aspirin together chronically, which has been shown to double the risk of gastrointestinal bleeding, and almost 30% of gastrointestinal bleeding is associated with the use of aspirin alone.4,10,11 In addition , 29% of the population The population believes that the use of OTC NSAIDs is safer than the use of prescription NSAIDs, and 40% of NSAID users report taking NSAIDs without a prescription, in addition to their NSAIDs.
A major weakness in the comparison of the toxicity of opiates and NSAIDs is that the use of opioids and attributable mortality is closely followed, however the toxicity of NSAIDs is based on estimates. Although the risk of gastrointestinal bleeding attributable to NSAID use has been studied, the increased risk of thromboembolic events or progression to end stage renal disease (ESRD) in NSAIDs is still unclear. However, it is important to remember that the FDA’s recommendations are based on a meta-analysis of high-dose NSAID treatment, the results of which indicate that increased cardiovascular risk is dose-dependent because selective cyclooxygenase (COX) -1 / COX-2 is lost at higher doses.
Despite these limitations, prevalence data make it reasonably clear that NSAIDs are more widely used with lower mortality than opioids, despite unrestrained and inappropriate use of NSAIDs. Physicians in all practice areas can make a significant difference by advising patients to recognize the risks of any use of NSAIDs in gastrointestinal and CV disease. They should advise patients to avoid concomitant use of prescription drugs and OTC NSAIDs and aspirin, and should provide strategies for gastric protection, if appropriate.
Myth number 2:
Prolonged-release opioids are more dangerous than immediate-release opioids
Is 30 mg of morphine extended release somehow more potent than 30 mg of immediate release morphine? And if it is not more potent, then the dulling of maximum concentrations (Cmax) slowly releasing the same amount of medication over a period of 10 to 12 hours (instead of immediate onset in 1-2 hours and elevated Cmax) do more dangerous? Conceptually, the idea is absurd. However, the interpretation of several studies has recently backed these exact conclusions.
Studies have shown an increased risk of adverse effects in patients with prolonged-release opioids. However, these studies often define chronic pain inappropriately and / or do not adjust for post-surgical pain and acute pain prescriptions. Patients with chronic pain tend to be in opioids much longer than patients with acute pain, and there is no doubt that longer exposure will lead to an increase in adverse effects.
Similarly, data from a recent study indicate that the rate of overdose increases dramatically in the first 2 weeks of treatment with prolonged-release opioids. This led the authors to the inappropriate conclusion that the pharmaceutical form itself is more dangerous and that short-acting opioids should be used if possible.15 This erroneous conclusion should have been recognized as an obvious struggle by current health care providers With appropriate equianalgesic conversions. When opioid rotations are performed.
Raising dosages due to unfamiliarity with some sustained release dosage forms is much more dangerous than the actual dosage form. For this reason, guidelines for chronic opioid therapy recommend finding the correct dose with immediate-release opioids prior to conversion to an extended-release regimen. In addition, patients receiving prolonged-release opioids tend to be at higher doses and are more ill, with many comorbidities. They are also often in concomitant therapies, including benzodiazepines, compared to patients with acute pain in immediate-release opioids, who might otherwise be young and healthy.
The old adage, “starts low and goes slow,” remains the safest way to approach initiation, titration, or rotation of pain medications. This is an example when physicians can have a tremendous impact and save lives through the experience of performing accurate equianalgesic conversions as well as educating others on dose reduction for cross tolerance and the identification of dangerous increases in Unintentional doses.
Myth number 3:
NSAIDs should be stopped 7-10 days before surgery or interventional procedures
Interruption of NSAIDs 7 to 10 days prior to surgery (or procedures) is commonplace, but is not evident. Stopping analgesics NSAIDs 1 week before interventional procedures is counterintuitive considering that NSAIDs mitigate the pain for which the intervention is indicated.
This recommendation reflects concerns about the risk of perioperative bleeding and assumes that all NSAIDs have the same risk of bleeding as aspirin.19 But aspirin is highly selective for COX-1 and binds Ser529, acetylating the binding site to The NSAIDs, causing irreversible inhibition that affects platelets more than other types of cells. This is because they are anucleated and remain inhibited throughout their life cycle (7-10 days) .
Relatively low doses of aspirin (
In the absence of evidence of risk of true hemorrhage from each NSAID, it is recommended that discontinuation prior to a procedure or surgery be made on the basis of pharmacology and pharmacokinetics. For example, NSAIDs with short half-lives such as ibuprofen (2 hours) or diclofenac (2.3 hours) would be completely eliminated after 5 half lives and less than 24 hours.
Even NSAIDs with longer half-lives such as meloxicam (15-20 hours) or naproxen (12-17 hours) would be completely eliminated within 4 to 5 days.19 The American Society of Regional Anesthesia and Pain Medicine and the American College Of Chest Physicians’ Evidence-based guidelines recommend the use of 5 half-lives of elimination as the basis for discontinuation prior to a procedure or surgery.
While many surgeons and interventionists certainly believe that caution is appropriate, many patients with pain turn to NSAIDs for mobility and disruption for some unnecessary days and have a significant impact on their daily lives.25 We must defend individualized attention Patient instead of one size-services-all medicine.
Myth number 4:
Suboxone naloxone prevents abuse when used off-label for pain
The naloxone component of Suboxone (buprenorphine with naloxone) was approved as maintenance treatment for patients with opioid abuse disorder. The addition of naloxone to the formulation was conceived as an abuse deterrent to discourage intravenous abuse, but its effects are minimal and of short duration. Both naloxone and buprenorphine can induce abstinence if given while taking a pure μ opioid agonist.
Suboxone contains a 4: 1 ratio of buprenorphine to naloxone, giving buprenorphine a concentration advantage that is largely unnecessary for opioid dependence. Buprenorphine has a 2 to 3-fold higher binding affinity for the receptor opioid compared to naloxone and a half-life which is 7 times longer. Even when abused intravenously, the only advantage that naloxone has over buprenorphine (in binding to opioid receptors) is the Fast. This is due to the unique pharmacodynamic profile of buprenorphine, which results in very slow kinetics with slow association (30 minutes) and extremely slow (166 minutes) and incomplete (50%) dissociation of opioid receptors, Displacement by other opioids is almost impossible. Upon reaching the receptor site, buprenorphine readily displaces naloxone, essentially rendering naloxone unnecessary. Therefore, the dissuasion advantage of naloxone abuse is short-lived.
For example, buprenorphine displaces an equal 90% fentanyl concentration of opioid receptors. However, unlike fentanyl, it takes 40 times the naloxone concentration in reverse. Suboxone 2 mg / 0.5 mg results in a saturation of the receptor from 36% to 50% and 16 mg / 4 mg as a result A saturation of 79% to 95% opioid receptors Buprenorphine.
One study allowed participants to challenge Suboxone (given in several doses) with IV hydromorphone 24 mg. The results of the study found that Suboxone 16 mg was highly effective in drastically reducing euphoria in 75% of patients.33 Delayed receptor binding kinetics are thought to contribute to decreased euphoria with buprenorphine compared to μ agonists Pure opioids. But it is clear that naloxone can not block or eliminate buprenorphine from exerting its pharmacological effects.
The superior pharmacology and superior kinetic profile of buprenorphine confer the deterrence of abuse associated with Suboxone and not the naloxone packaged with it.
Myth Number 5:
Butrans patches can increase a patient’s QTc interval
The buprenorphine transdermal delivery system (BTDS) has not been shown to increase QTc intervals to a clinically significant level at doses below 40 mcg per hour. Frankly, the FDA’s decision not to allow doses greater than 20 mcg per hour is highly questionable and too conservative.
The current FDA approved pamphlet indicates that patches of 40 mcg per hour (2 x 20 mcg / h) resulted in a mean change in QTc prolongation of 9.2 ms (range, 5.2-13.3) , Any value greater than 5 ms is considered positive) The results reported in the trial itself had QTc prolongations of 6.01 ms (3.2-8.8) when calculating the difference with placebo34,35. However, the placebo arm of the study showed increases in QTc as high as 5.7 ms, which is beyond the threshold of concern cited by the current FDA guidance. Should we ban placebo from trials as a comparator based on this “evidence”?
This question becomes clinically significant for another reason-in essence, it severely limits the use of a very useful dosage form, particularly for patients struggling with compliance, but they have complaints of legitimate pain. To illustrate, BTDS has been available internationally since 2001 and is widely used in Europe in a variety of dosage forms (35 mcg / h, 52.5 mcg / h and 70 mcg / h). The lowest internationally available dose, therefore, is higher than the highest dosage form currently available in the United States.
It is also important to keep the relative dose of buprenorphine in perspective. Sublingual products containing buprenorphine are available in 2 formulations: Subutex (buprenorphine alone: 2 mg and 8 mg Note: Subutex is no longer available but the generic version of buprenorphine is on the market) and Suboxone (buprenorphine / naloxone: 2 mg / 0.5 mg, 4 mg / 1 mg, 8 mg / 2 mg, and 12 mg / 3 mg). The sublingual dose of 2 mg of Suboxone is approximately equivalent to the 20 mcg patch per hour, factoring in an absorption of 30% .27 This seems to imply that sublingual buprenorphine, which is commonly used in doses between 16 and 32 mg per day, Is being treated differently from transdermal products simply because the intended population is different.
There are many studies evaluating the QTc prolongation of sublingual buprenorphine compared to methadone. Suboxone is often recommended as an alternative to methadone for maintenance therapy when a person’s QTc is greater than 500 ms-placing the patient at risk of torsades de pointes (TdP) and sudden death.37 In fact, it is rare , Even in long-term studies of buprenorphine, to see mean prolongation of QTc greater than 12 ms (+/- 4.1) despite high-dose therapy (16-32 mg), or QTc intervals greater than 450 ms without Some genetic abnormality or drug interaction, particularly with chromosome P450 CYP) 3A4-none of which are routinely evaluated in clinical practice.
The decision to enforce such a low QTc prolongation threshold needs to be re-examined with emphasis on clinical relevance because this becomes a significant barrier to drug approval. The FDA plans radical changes in the drug approval process for opiates; however, many of the drugs we currently depend on would not be approved in the current environment, suggesting that it may be time to re-examine certain drug decisions. FDA.