It has been known for centuries that opioids are highly addictive when consumed for prolonged periods of time. Pharmacologic tolerance to the efficacy of opioid analgesic results in a need for increased dosing and drug dependence. One must question the empirical sources of evidence that justified the belief that prescription opioids were safe and effective for treating acute and chronic pain. Progress in developing and applying evidence-based analgesic therapies for acute inflammatory pain is presented.
Key points
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Historically, recommendations for pain management relied on practitioner experience, with little valid clinical research available.
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The era of randomized placebo-controlled clinical trials using third-molar extraction surgery greatly expanded our understanding of analgesic efficacy and safety.
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Meta-analyses of data from more than 460 clinical analgesic trials allow clinicians to compare the benefits and harms associated with analgesics used for acute pain.
North America is facing an escalating opioid addiction crisis that was created to a great extent by inappropriate prescribing of opioid analgesics for the management of pain. During the 1990s, various advocacy groups lobbied the medical community to improve chronic pain management in the United States. These patient groups estimated that millions of people were unnecessarily suffering because of failed or inadequate treatment of their chronic pain. The medical community responded, with support of The Joint Commission, by establishing pain as the “fifth” vital sign and recommended that all patients, as part of routine evaluation, should, in addition to recording blood pressure, pulse, respiratory rate, and body temperature, be queried regarding possible pain symptoms. It was thought that identifying and prioritizing patients’ pain symptoms would promote better chronic pain management. Unfortunately, recognizing patients’ pain condition without the availability of evidence-based treatments did not necessarily translate into better treatment.
As a strategy to better manage chronic pain, the medical community began using more opioid analgesics, particularly delayed-release formulations, to provide pain relief. Opioid prescribing increased tenfold during the period of 2000 to 2016. This dramatic increase in prescription opioids resulted in an increase in the availability and subsequent misuse of these addictive pain medications. This misuse and abuse of opioid analgesics has been shown to be closely correlated with increased emergency department visits for overdose reactions.
It has been known for centuries that opioids are highly addictive when consumed for prolonged periods of time. Pharmacologic tolerance to the efficacy of opioid analgesic results in a need for increased dosing. The more recently described phenomena of opioid-induced hyperalgesia whereby some patients actually become more sensitive to pain-provoking stimuli further adds to the quandary. One must question the source of evidence that justified the belief that prescription opioids were safe and effective for treating chronic pain.
Pain management has historically relied on clinical experience that emphasizes the “art” component of the accepted “art-and-science” approach to medicine. Essentially only 3 drugs were considered effective pain relievers before 1970: aspirin (ASA), acetaminophen (APAP), and agents derived from opium (eg, morphine, codeine). Selection of an agent and determination of proper doses were empirical and relied on clinical knowledge and the accepted principles of “in-my-hands” recommendations. Formal scientific assessments of efficacy and safety were uncommon; placebo-controlled studies were rare; analgesic therapies focused mainly on hospitalized patients with cancer pain, headache, and postsurgical pain, such as episiotomy. Well-established clinical evidence for analgesic efficacy and safety was lacking.
A letter to the editor in the New England Journal of Medicine : 1980
Long-acting opioids, such as Oxycontin®, one of the most notoriously abused delayed-release opioids ever marketed, were promoted as safe treatments for managing chronic non-cancer pain by their pharmaceutical manufacturers. With little clinical evidence, delayed-released opioids were presented to the medical community as being able to establish relatively constant blood levels, so that cravings for re-administration, that may be associated with rapid drug elimination and rapid lowering of opioid blood levels, would not occur. The dangers of opioid drug dependence were downplayed, in part, by relying on scant evidence such as the letter to the editor of the New England Journal of Medicine published in 1980. This short, 101-word letter sent by Jane Porter and Hershel Jick of the Boston Collaborative Drug Surveillance Program was misrepresented to imply that addiction and dependence associated with opioid analgesics was rare (4 patients of 11,882 hospital patients examined).
The letter is available in its entirety from the New England Journal of Medicine . It has been reproduced on several websites, a book entitled Dreamland by Sam Quinones describing the development of the current opioid crisis, and most recently in a thoughtful letter in the New England Journal of Medicine that critically addressed the 608 citations and the overall misuse of Porter and Jick’s observation within the medical community. See https://www-nejm-org.easyaccess1.lib.cuhk.edu.hk/doi/10.1056/NEJM198001103020221 .
This brief “letter to the editor” was written to provide a rapid unstructured observation of the narcotic addiction potential when immediate-acting opioids are administered in a physician controlled and monitored hospital environment, provided for treatment of acute pain, and given to patients with no history of drug addiction. It was never intended to be a scientific study. It was never intended to describe addiction risk associated with unsupervised administration outside of a hospital environment. It was never able to suggest addiction potential with chronic administration.
Elements of the 101-word letter included:
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The 11,882 patients included were all “hospitalized medical patients.”
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“…we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients’ who were monitored consecutively.”
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Patient demographics, selection criteria, or opioid regimen are not provided.
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“…there were 11,882 patients who received at least one narcotic preparation.”
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Definitions and diagnoses of “addiction” or “history of addiction” were not stated.
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“…there were only four cases of reasonably well documented addiction in patients who had a history of addiction.”
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The concluding sentence makes it clear that the abstract was not describing long term administration of opioids for treating chronic pain in an unsupervised outpatient setting.
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“….despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.”
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As a brief letter, the duration of hospital stay and reason for these medical patients’ hospitalization are not provided.
The Boston Collaborative Drug Surveillance Program was a hospital-based program that assessed drug side effects among post-operative and burn inpatients, and had little capability to identify, evaluate and document the addiction potential of long-term outpatient opioid therapy. Clearly the observation had been drastically misinterpreted when considering chronic pain patients. Its impact may have been due to the prestige of the New England Journal of Medicine where this letter to the editor was published. Certainly, the importance and relevance of the letter was incorrectly presented as valid evidence for the safe and non-addictive use in treating chronic pain.
Thankfully, the requirements for evidence-based analgesic therapy have changed.
Randomized placebo-controlled clinical trials for pain assessment
A major contribution to our knowledge of the safety and efficacy of oral analgesics comes from an outpatient methodology described by Steve Cooper and William Beaver during the 1970s. These clinical pharmacologists developed and validated a method to assess the efficacy of analgesics for pain relief following the common outpatient dental procedure of third-molar (wisdom tooth) extraction. The postoperative pain model demonstrated sensitivity in distinguishing oral analgesic medications from placebos and other active drugs. The availability of such a large potential population requiring acute postoperative pain management facilitated the utility of this clinical pain model.
The power of the model for collecting clinical trial data regarding analgesic safety and efficacy was based on its straightforward categories for recording pain intensity and pain relief, the reasonably homogeneous nature of the surgical trauma of the third-molar extraction procedure, and a large population of young, healthy subjects available for enrollment. It has been estimated that 3.5 million young adults undergo the extraction of their wisdom teeth every year in the United States.
As newer nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen and naproxen, were being developed in the 1970s through the 1990s, this efficient pain assessment model was commonly employed. The model was accepted by the Food and Drug Administration (FDA) to demonstrate the efficacy and safety indications for new analgesic drug applications. This placebo-controlled clinical drug trial model has been used, with some variation and modification, for almost all of the analgesics marketed today in North America.
The clinical pain model enrolls subjects planning to undergo third-molar extractions. To assure adequate surgical trauma, most clinical trials require at least one of the teeth to be impacted within the lower jaw bone (mandible). This outpatient surgical procedure requires local anesthesia and often an intravenous sedation regimen and is completed for all enrolled subjects. Following surgery, as the local anesthesia wears off and pain intensity reaches a moderate to severe level, subjects are provided one of several blinded treatment options, usually in a parallel design. In addition to a placebo, the research design usually includes a known comparator (ie, acetaminophen) and the medications to be evaluated. A rescue medication is provided if subjects have pain that is not adequately managed by their treatment medication.
Pain is assessed before any of the drug treatments are administered and at hourly intervals. Pain intensity is recorded using categories of severe (3) moderate (2) slight (1) and or none (0). Pain relief is recorded hourly as complete (4) a lot (3) some (2) a little (1) or none (0). The pain intensity measures are transformed into pain intensity difference (PID) from baseline. For example, Fig 1 illustrates the mean hourly responses of each PID measures over the period of study. Summary statistics for the drugs’ overall effectiveness often uses the sum of all hourly PIDs weighted over time [SPIDs] and the sum of hourly pain relief scores weighted over time [TOTPARs].
