Recent advances in acute pain management: understanding the mechanisms of acute pain, the prescription of opioids, and the role of multimodal pain therapy

“Nobody can go back and start a new beginning but anyone can start today and make a new ending.”

Maria Robinson

Introduction

The over-prescription of opioids and the exclusion of other non-opioid options have contributed to a national opioid epidemic crisis. It is estimated that the use of opioids costs over $700 billion annually. In the wake of the opioid crisis, various federal and non-federal agencies introduced stricter guidelines to address prescription practices and prevent this situation from getting worse.

A recent CDC report indicated that medical prescriptions of opioids peaked in the US in 2010 and have declined each year since, while in contrast opioid overdose deaths continued to rise. The most recent increase in the use of opioids is widely attributed to the illicit non-medical use of heroin, fentanyl, and now carfentanyl (50 times more potent than fentanyl).

The CDC report indicated that the dose and duration of the treatment represented important factors leading to addiction. In this report, it was also suggested that a treatment as short as 10 days can lead to opioid dependency. Recent data also suggested that up to 15% of surgical patients may become dependent following the perioperative use of opioids. This re-enforces the recommendation of limiting the amount of opioids used during the perioperative period and favors a multimodal approach that includes regional anesthesia.

Pain is multidimensional in nature, injury is just one cause of pain, and various factors play a role in the pathogenesis of pain. In recent years, the role of psychosocial factors in the level of pain experienced by patients undergoing surgery has been at the forefront of research.

Remodeled pain management guidelines

In the wake of the prescription opioid abuse crisis, the American Pain Society (APS) and the American Society of Anesthesiologists (ASA) have developed a comprehensive evidence-based guideline for postoperative pain management. Of the numerous recommendations, four were considered high-quality evidence and hence strongly recommended¹.

There has also been a need for classifying the multidimensional aspect of pain. Recently, a task force on the taxonomy of acute pain by the APS and the American Academy of Pain Medicine (AAPM) has come together to standardize the clinical diagnostic criteria for pain².

The group proposes a five-dimensional approach to describe acute pain conditions:

Such a complex approach clearly reflects on the multidimensional nature of acute pain, the complexity and diversity of the mechanisms involved, and the tissue’s specificity of the response to an “insult”².

Psychosocial factors contributing to pain

A meta-analysis reviewing the literature on the role for anxiety and pain catastrophizing (defined as the tendency to magnify/dread the pain and feel helpless in the context of pain) concluded that there is good evidence that psychosocial factors play a major role in the development of chronic pain³.

A very recent trial called the SCOPE trial (Stepped Care to Optimize Pain care Effectiveness) studied the independent effects of depression, anxiety, and pain catastrophizing on pain outcomes. The authors found that improvements in depression, anxiety, and pain catastrophizing predicted reductions in pain intensity and pain-specific disability. It has also been concluded that prior operative improvement in depression, catastrophizing, and anxiety has positive benefits. Accordingly, it seems that depression is the most important factor, followed by pain catastrophizing, and anxiety is last. Also, the beneficial effects of psychological improvement on pain outcomes were significant, even after adjustment for the effects of the optimized analgesic intervention⁴.

Preoperative risk factors were thought to predict pain catastrophizing and depression in patients scheduled to have joint surgery. At-risk patients were those with high preoperative pain scores in the presence of good objective clinical function; in addition, those who subjectively rated increased pain and poor function, younger patients, females, and patients with multiple comorbidities are also at significant risk for hospital anxiety and depression⁵.

A recent clinical practice guideline from the American College of Physicians stresses the importance of using integrative health modalities in treating patients with low back pain. Therapies given strong recommendations were mindfulness-based stress management⁶, acupuncture, exercise, and multidisciplinary rehabilitation⁷. The concept of multidisciplinary rehabilitation involves bringing several healthcare providers together and targeting different dimensions of recovery like pain relief, functional restoration, improvement of psychological distress, or improvement in work ability of chronic pain/opioid-dependent patients⁸. The challenge is bringing this degree of care to the primary care level. Learning from the Swedish example, where medical clinics were offered a financial incentive for every patient who completed a rehabilitation program, might facilitate access to enhanced rehabilitation services⁸.

Multimodal pain therapy

Multimodal analgesia involves the concurrent use of primarily non-opioid analgesics to take advantage of the additive, if not synergistic, effects that produce superior analgesia while decreasing opioid use and opioid-related side effects⁹. Also a key component of multimodal pain management is the utilization of regional analgesic techniques, including peripheral and field blocks and neuraxial blocks (epidural analgesia, for example).

The ASA task force on acute pain management in 2012 recommended that multimodal pain management should be included for the management of perioperative pain whenever possible. The ASA task force members recommended that acetaminophen should be considered an integral part of a postoperative multimodal pain management regimen and that cyclooxygenase (COX)-2-selective NSAIDs, non-selective NSAIDs, and calcium channel α-2-δ antagonists (gabapentin and pregabalin) should be considered as part of a postoperative multimodal pain management regimen. Moreover, guidelines suggest that patients should receive an around-the-clock regimen of NSAIDs or acetaminophen. Whenever the patient’s characteristics allow, regional blockade with local anesthetics should be considered as part of a multimodal approach for pain management¹⁰. Other potential drugs to be used include steroids, α-2-agonists such as clonidine and dexmedetomidine, N-methyl-D-aspartate (NMDA) receptor antagonists, with ketamine as the primary example, but also dextromethorphan, and magnesium administered locally, intravenously (IV), and/or as a part of the local anesthetic mixture. However, it should be recognized that to date the efficacy of a given “cocktail” has not been studied. The principles behind the use of such “cocktails” are really theoretical. This is probably an area of research that deserves the most attention.

History of the opioid epidemic

In 2000, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) released standards for pain management, including the introduction of pain scales in recovery rooms and criteria of an acceptable pain score for discharge. The concerns regarding these new standards peaked after it led to an over-prescription of opioids in many hospitals. In response to this issue, the JCAHO, in 2001, declared that pain should be considered the fifth vital sign, a statement which would later be removed from subsequent recommendations²⁸. However, it did not help that pharmaceutical marketing initiatives notified doctors that a safe drug (OxyContin) was available to treat chronic pain²⁹ and that this drug could not be misused/abused because of its formulation. It was not until 2007 that Purdue pleaded guilty to federal criminal charges of misleading doctors when it claimed OxyContin is less likely to be abused²⁹.

Although, OxyContin is approved for only chronic pain, the drug is often prescribed during the perioperative period to “reduce” the dose and frequency of short-acting opioids. Frequently, 10–20 mg of OxyContin is ordered to be administered immediately prior to surgery and until discharge.

The above factors played a significant role in the development of the opioid epidemic as we see it today. Per the 2015 National Survey on Drug use and Health, about 2.7 million people aged 12 or older had a prescription drug use disorder in the past year (Figure 1). In 2015, 822,000 people received treatment for the misuse of pain medications³⁰. What was most disturbing is that 34% of misused prescription opioids come from legitimate physician medical practice offices (Figure 2). Opioid overdose is now the first leading cause of accidental death in the United States, surpassed only by motor vehicle accidents³¹.

Figure 1. Numbers of past year prescription psychotherapeutic users among people aged 12 or older: 2015³¹.

NSDUH, National Survey on Drug Use and Health.

Figure 2. Source where pain relievers were obtained for most recent misuse among people aged 12 or older who misused prescription pain relievers in the past year: percentages, 2015.

Per a recent morbidity and mortality report released by the CDC (Centers for Disease Control and Prevention), an opioid-naïve patient showed increase risk for chronic opioid use with each additional day of medication supplied, starting with the third day, with the sharpest increases in chronic opioid use after the fifth and thirty-first day on therapy. The CDC recommends that prescribing physicians evaluate the need for a second prescription³².

In surgical subpopulations, the following patients are at higher risk for opioid addiction/dependence³³: those who are younger, have low socioeconomic status, have preoperative pain and comorbidities (pulmonary disease, heart failure), abuse substances or tobacco, and are on specific pharmaceuticals (like benzodiazepines).

Opioid dependence treatment programs

The four medications available for opioid dependence are methadone, buprenorphine, naloxone, and naltrexone, alone or in combination. Even though they are effective treatments, more often patients switch their addiction from one opioid to another and thus are unable to emerge from the vicious cycle of opioid dependence³⁴. The newest implant approved by the US Food and Drug Administration (May 2016) is Probuphine^®, which delivers steady-state levels of buprenorphine over 6 months. Numerous studies have demonstrated its efficacy and safety³⁴.

The present recommendation includes a medication-assisted treatment provided by an opioid treatment program. It combines behavioral, cognitive, and pharmaceutical therapies. Since it is clear that there is a shortage in the number of treatment centers in the country, consideration has been given to training and permitting primary care physicians to prescribe buprenorphine, thus increasing treatment accessibility³⁵.

Another barrier to be recognized is the fact that many of these patients don’t have medical insurance and therefore are directly responsible for the cost associated with it. There is no doubt that offering universal medical insurance access would allow many more patients to access opioid addiction programs readily.

There are two proposed approaches on how to manage these patients in the case of scheduled surgery: the most logical approach is to transition the patient from an opioid partial and/or complete antagonist to a full opioid agonist 2–5 days before surgery, continue the use of opioids as needed during and immediately after surgery, and transition back to their original protocol 2–5 days following surgery. The second approach simply recommends no interruption in the treatment and increasing the perioperative dosage of opioids accordingly to overcome the blockage. It is also what happens when urgent surgery is required. It should also be noted that the management of these patients is often complicated by the facts that 1) several patients take it upon themselves to stop their treatment (go “cold turkey”) and come to surgery in acute withdrawal and 2) they often don’t want to preoperatively disclose their addiction.

Enhanced recovery after surgery pathway

In the past few years, care guidelines have been developed to take a comprehensive approach to enhance recovery after surgery (ERAS). The ERAS pathway is founded on evidence-based measures taken perioperatively to promote faster recovery after surgery. This is not only about surgery-related elements but also about the anesthesia plan, pain management, nursing, physical therapy, and nutrition³⁶. Prior to surgery, it includes physical optimization, counseling, avoidance of preoperative bowel preparation, limited fasting, and preoperative intake of carbohydrate-rich drinks. The anesthesia is characterized by the intraoperative use of short-acting anesthetics and the limited use of opioids, the perioperative period focus on the prevention of thromboembolism and antibiotic prophylaxis, and effective analgesia. Restricted fluid therapy, prevention of hypothermia, prevention of PONV, pain management based on non-opioid drugs, early enteral nutrition, stimulation of gastrointestinal motor activity, limited use of naso-gastric tubes and post-operative drains when possible, and early mobilization and removal of urinary catheters complete ERAS strategies³⁷. There is a special emphasis on the use of regional anesthetic techniques to minimize the perioperative use of opioids. Epidural and peripheral nerve and field block protocols have been developed to achieve effective perioperative pain management and prevent postoperative ileus. In this respect, local anesthetic solutions devoid of narcotics are recommended.

Several observational studies comparing pre-ERAS with post-ERAS opioid intake have noted a substantial decrease in inpatient opioid consumption with the implementation of an ERAS pathway in a variety of surgical procedures⁹.

Molecular mechanisms of acute pain

TRPA1 receptors are involved in the guarding deep tissue pain resulting from the incision of the fascia and muscles but not of the skin³⁸. Previously, Choi et al. provided evidence in support of the presence of TRPV1 receptors in the central nervous system and their involvement in neuropathic pain. It appears that an upregulation of the central nervous system TRPV1 receptors represents a key mechanism in the transition of acute to chronic pain³⁹. In this regard, Mickle et al. demonstrated that the upregulation of the TRPV1 receptors led to thermal and mechanical hypersensitivity modulated by parathyroid hormone-related peptide⁴⁰.

Into the future of pain medication prescribing: pharmacogenetics

A variety of genes impact narcotic and non-steroidal (NSAID) drug efficacy, including the CYP family (drug metabolism) or catechol-O-methyltransferase (COMT)/ABCB1/OPRM1 (functional receptor and transport activity for analgesia versus side effects)⁴¹.

CYP2D6 plays an important role in metabolizing analgesic pro-drugs to their active narcotic metabolite, such as codeine, tramadol, and dihydrocodeine. Alterations in CPY2D6 manifest phenotypically as poor, intermediate, extensive, and ultra-rapid metabolizers⁴¹.

The COMT gene encodes the enzyme believed to moderate the transmission of pain signals via the removal of catecholamine (i.e. dopamine, epinephrine, and norepinephrine). Reduced COMT activity appears to be related to increased pain sensitivity⁴².

P-glycoprotein transporter (P-gp) coded by the ABCB1/MDR1 gene is an efflux transporter. It is a major determinant of the bioavailability of many opioids such as fentanyl, sufentanil, alfentanil, morphine-6-glucuronide, and morphine-3-glucuronide. P-gp is capable of limiting the entry of some opiates into the brain and pumping a variety of drugs out of the central nervous system. It is thus an important constituent of the blood–brain barrier⁴³.

The μ-opioid receptor is coded by the gene OPRM1. Genetic substitutions in this gene can cause patients to require higher morphine doses and systemic drug narcotic levels for effective analgesia. All of the above genes can be pharmacogenetically tested via buccal swab⁴¹.

Conclusion

In the field of acute pain, the bigger pain management challenges facing the medical community are threefold. First is reaching out to primary care doctors and surgeons (where a large portion of the narcotic prescriptions are originating) and re-educating them on appropriate pain management techniques, including the use of a multimodal approach to decrease and/or eliminate the use of opioids. In this respect, it is critical to incorporate postoperative pain management as a core competency during the training period of primary care doctors and surgeons³³. It is also critical to continue our efforts towards “opioid free anesthesia and postoperative analgesia” by significantly reducing or eliminating, when possible, opioid use in hospitals and clinics around the country⁴⁴. Second is expanding access to opioid addiction treatment programs—these programs save lives. Third is promoting research and development related to the treatment of opioid addiction via the development of new formulations such as Probuphine and Xtampza^® ER (oxycodone) based on the use of higher concentrations of the active ingredient mixed with abuse-deterrent elements, which prevents diversion of the drug to a liquid form for IV injection. It is also important to continue the search for the “Holy Grail”, which in the case of opioids is a “non-addictive opioid”.