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Reimagining How We Treat Acute Pain: A Narrative Review

Pablo castroman, ovelio quiroga, victor mayoral rojals, maria gómez, joseph pergolizzi jr, giustino varrassi.

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Giustino Varrassi [email protected]

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Received 2022 Mar 1; Accepted 2022 Apr 6; Collection date 2022 Apr.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Acute pain may be influenced by biopsychosocial factors. Conditioned pain modulation, distraction, peripheral nerve stimulation, and cryoneurolysis may be helpful in its treatment. New developments in opioids, such as opioids with bifunctional targets and oliceridine, may be particularly suited for acute pain care. Allosteric modulators can enhance receptor subtype selectivity, offering analgesia with fewer and/or less severe side effects. Neuroinflammation in acute pain is caused by direct insult to the central nervous system and is distinct from neuroinflammation in degenerative disorders. Pharmacologic agents targeting the neuroinflammatory process are limited at this time. Postoperative pain is a prevalent form of acute pain and must be recognized as a global public health challenge. This type of pain may be severe, impede rehabilitation, and is often under-treated. A subset of surgical patients develops chronic postsurgical pain. Acute pain is not just temporally limited pain that often resolves on its own. It is an important subject for further research as acute pain may transition into more damaging and debilitating chronic pain. Reimagining how we treat acute pain will help us better address this urgent unmet medical need. 

Keywords: persistent postsurgical pain, multi-modal therapy, biopsychosocial factors, pain chronification, pain management, chronic pain, acute pain

Introduction and background

Acute and chronic pain are often differentiated temporally with acute pain being of shorter duration, but their underlying mechanisms are fundamentally different. Acute pain occurs when noxious stimuli perceived by the peripheral nervous system are transmitted and along the way modulated by the central nervous system. On the other hand, chronic pain is associated with aberrant pain signal processing and interpretation and, as such, is much more challenging to treat. Cerebral neuroplasticity may cause maladaptive changes with persistent pain, inducing peripheral and central sensitization. Prompt and effective treatment of acute may interrupt potential pain chronification, which involves a complex interplay of ion channels, receptors, neurotransmitters, and neural systems [ 1 ]. Thus, the transition from acute to chronic pain involves a transition of the underlying pain mechanisms [ 2 ].

Pain intensity can be assessed using validated tools, but they offer only a unidimensional measurement of the pain; in reality, even acute pain can be complex and colored by biopsychosocial factors [ 3 ]. Acute pain is often is far more complex than previously realized and its effective treatment of far greater importance than previously realized. It is therefore time to reimagine how we treat acute pain. This is a narrative review based on proceedings from a conference in Lima, Peru, held in October of 2021.

It is difficult to overstate the global prevalence of acute pain, which is the main reason for up to 70% of visits to emergency departments [ 4 ]. Acute pain is a primary reason for visits to the doctor and many hospitalized patients experience acute pain during their stay [ 5 ]. Acute postsurgical pain, which occurs in about 80% of surgery patients, is a common form of acute pain and can be severe. Over a third (38%) of unexpected hospital readmissions following ambulatory surgery occur on account of pain [ 6 ].

Promising new treatment options for acute pain are emerging from translational pain medicine. The sensory experience of acute pain is surprisingly complex because the interactions between afferent inputs and their processing across the peripheral and central nervous systems involve affective-motivational components [ 7 ]. The acute pain experience is dynamic because it may be colored by a variety of fleeting and long-term psychological and psychosocial factors. The old stimulus-response view of acute pain is outmoded; in reality, pain signaling, like the experience of pain, is far more nuanced. The old theory that the experience of pain began in the thalamus of the brain has given way to the newer idea that the perception of pain arises in the cortex of the brain, albeit with certain thalamic inputs [ 8 , 9 ].

Drug development for analgesics is complex because there is no single main target for these agents; the most familiar of these analgesic categories target different mechanisms. Many analgesics developed fail to be cleared for market release because they either lack efficacy and/or present adverse safety profiles [ 10 ]. Opioids, cannabinoids, N-methyl-D-aspartate (NMDA) modulators, and serotonin modulators target the central nervous system; voltage-gated sodium channel (NaV) inhibitors, NMDA modulators, calcium modulators, and gamma-aminobutyric acid (GABA) modulators also target the dorsal horn; and nonsteroidal anti-inflammatory drugs (NSAIDs), NaV inhibitors, nerve growth factor (NGF) modulators, and transient receptor potential cation channel subfamily vanilloid (V) member-1 (TRPV1) modulators work on the peripheral nervous system (Table 1 ) [ 10 ].

Table 1. The main analgesic drug classes currently in development.

GABA: gamma-aminobutyric acid; NGF: nerve growth factor; NMDA: N-methyl-D-aspartate; NSAID, nonsteroidal anti-inflammatory drug; TRPV1: transient receptor potential cation channel subfamily V member-1; NSAID: non-steroidal anti-inflammatory drug; NaV: voltage-gated sodium channel

Nonpharmacologic options may not always be considered for acute pain, but distraction has emerged as a viable method to reduce acute pain by diverting the finite attentional resources of the brain away from painful stimulation [ 11 ]. Emerging from these studies of distraction are the ideas that learning mechanisms, such as pain catastrophizing, can exacerbate pain, while pleasant distractions may intervene and blunt pain. Distraction as pain control is not well studied, but appears to be more effective in pediatric than in adult patients [ 12 , 13 ].

Conditioned pain modulation (CPM) describes the decrease in perceived pain intensity for one stimulus after the application of a conditioning stimulus to another area of the body [ 14 ]. CPM has interpatient variability and is not present in some patients at all. In a study of 54 healthy adults, eight noxious heat stimuli were applied to the right side of the mouth while brain activity was evaluated using magnetic resonance imaging (MRI). After the first series, the process was repeated, but after the fourth stimulus, a separate noxious stimulus was used in the form of an intramuscular injection of hypertonic saline solution into the leg as a conditioning stimulus. CPM was observed in 23/54 patients as measured by reduced pain intensity [ 15 ]. In another study using cold pressor pain, 93% of healthy subjects exhibited clinically meaningful CPM [ 16 ]. CPM may be seen as a natural form of pain protection, but it is unclear why it exists only in a subset of the population [ 17 ]. Certain medications may interfere with CPM [ 18 ].

Transcranial direct-current stimulation (T-DCS), often used to treat chronic painful conditions, is now being studied in acute pain. In a study of 55 post-thoracotomy oncology patients who had intercostal nerve blocks and patient-controlled analgesia (PCA) morphine after surgery, patients who received anodal T-DCS over the left primary motor cortex for 20 minutes at 1.2 milliamperes (mA) for five consecutive days consumed significantly less postoperative morphine and had 80% less pain with cough five days after surgery than those patients who were administered sham stimulation. One year after surgery, both groups were similar with respect to the incidence of chronic pain and analgesic consumption [ 19 ]. In another study, T-DCS following thoracotomy was found to be a cost-effective method of pain control [ 20 ]. 

Peripheral nerve stimulation (PNS), used to treat chronic pain, is likewise being re-imagined for its possible role in treating acute pain. PNS requires the insertion of a lead under ultrasonic guidance, through which electric current flows to stimulate the nerve(s). PNS is not approved in some regions of the world, and evidence in support of its role is better established in chronic than acute pain [ 21 ]. Recently, ultrasound-guided percutaneous PNS has been shown effective to help manage postoperative pain [ 22 ]. In a study of five patients who underwent total knee arthroplasty, percutaneous PNS reduced pain by a mean of 93% at rest, and 80% of patients reported that their pain resolved completely [ 23 ]. 

Cryoneurolysis refers to the direct application of cold to a peripheral nerve, causing what has been called “reversible ablation,” meaning that it allows Wallerian degeneration and nerve regeneration to occur [ 24 ]. Cold-delivery wires called cryoprobes are placed percutaneously or through the surgical incision; a hand-held activator is available to initiate therapy delivery. Already used to treat the chronic condition of spasticity, cryoneurolysis has been shown effective in reducing acute postoperative pain [ 24 ].

Opioids have long been recognized for their role in acute pain control in appropriate patients. Oliceridine is a next-generation intravenous (IV) opioid that acts as a G-protein selective agonist at the µ-opioid receptor, allowing it to reduce the recruitment of β-arrestin, associated with adverse events [ 25 ]. In a randomized phase IIb study, 200 patients undergoing abdominoplasty were randomized to one of four groups: IV oliceridine with a loading dose of 1.5 mg and patient-controlled (PC) demand dosing of 0.10 (regimen A), IV oliceridine with a loading dose of 1.5 mg and PC demand doses of 0.35 mg (regimen B), IV morphine 4.0 mg loading dose and PC de9999mand doses of 1.0 mg (regimen C), and placebo. Treatment began four hours after surgery and continued for the next 24 hours. Both oliceridine groups provided significantly better pain control than placebo and offered pain relief similar to that of morphine, but with a significantly lower prevalence of adverse events [ 26 ]. Fewer opioid-associated adverse events and some early evidence that oliceridine presents a lower risk for opioid-induced respiratory depression make this a promising new agent for acute pain [ 27 ].

Bifunctional opioids are those that target more than one opioid receptor [ 28 ]. Opioids may bind with high affinity to κ, δ, and/or the nociception/orphanin FQ peptide receptors (NOP). In theory, the affinity for multiple receptors could enhance analgesia while reducing adverse effects [ 28 ]. Of these bifunctional opioids, the most attention has been devoted to a novel agent, KGNOP1, which has an affinity for both the µ- and NOP-receptors [ 29 ]. KGNOP1 is structurally based on a µ-opioid-receptor agonist and a weak nociception receptor antagonist (KGNOP3) that was developed to provide both nociceptive and neuropathic analgesia in a single agent [ 30 ]. In a murine study, KGNOP1 was effective in reducing experimental forms of both nociceptive and neuropathic pain [ 30 ]. By contrast, cebranopadol, a first-in-class analgesic currently under clinical investigation, is a full agonist at the NOP receptor [ 31 , 32 ]. 

Allosteric modulators are substances which, when binding to a particular receptor, change the receptor’s conformation and thereby increase or decrease its affinity for other molecules. For opioids, the recent discovery of specific allosteric ligands for G-protein-coupled receptors (GPCRs) may help with receptor subtype selectivity and could reduce potentially treatment-limiting opioid-associated side effects [ 33 ]. Positive allosteric modulators bind to sites on the µ-opioid-receptor different from the orthosteric site, where endogenous agonists bind. In the absence of the orthosteric agent, these positive allosteric modulators have only negligible effect, but they are capable of increasing or decreasing the potency of the orthosteric agonist [ 34 ]. Positive allosteric modulators are selective, and even related receptors of the same family may have different binding sites [ 35 ]. Allosteric agents targeting GPCRs allow for potentiation of allosteric modulation or negative allosteric modulation (NAM), but some Positive allosteric modulators also work with endogenous ligands. Moreover, there may be bitopic ligands that interact with both orthosteric and allosteric sites [ 36 ]. Allosteric modulation of GPCRs may be useful in the treatment of neurodegenerative disorders, such as Alzheimer’s disease and psychiatric illnesses such as schizophrenia [ 36 ]. Allosteric modulators have been found for µ-, δ-, and κ-opioid receptors, but no allosteric modulator has been found to date for NOP receptors. A study in a mouse model found the µ -opioid-receptor potentiation of allosteric modulation agent, BMS-986122, enhanced the ability of the endogenous opioid methionine-enkephalin to cause G-protein activity in the brain without any activity of its own, allowing greater inhibition of GABA release into the periaqueductal gray matter. The novel potentiation of allosteric modulation agent BMS-986122 does not bind to the orthosteric site and does not act as a µ-opioid-receptor agonist; for those reasons, it has fewer and milder side effects compared to conventional opioids [ 35 , 37 ].

Spahn and colleagues are investigating whether using the pathological conformation dynamics of opioid receptors - rather than physiological conformation - might affect the way opioid receptors interact with their ligands, specifically whether this interaction might occur without adverse effects [ 38 ]. Using computer simulations at low pH levels, they designed a selective agonist for the peripheral µ-opioid receptors near the site of injury and found this candidate agonist exhibited marked pH-sensitive binding in contrast to pharmaceutical fentanyl. In a murine study, this agent provided injury-specific analgesia without opioid-associated side effects [ 38 ].

The many voltage-gated ion channels in the body are transmembrane proteins that play important and varied roles. In particular, many subtypes of voltage-gated sodium (NaV) channels appear to be important in peripheral pain signaling. Loss-of-function mutations of NaV1.7 result in congenital insensitivity to pain, so NaV1.7 became an interesting new target for a pharmacologic antagonist [ 39 ]. Since such polymorphisms are rare, clinical investigative opportunities are limited. New data emerging suggest that any agent seeking to recapitulate the effects of a loss of function of NaV1.7 will have to penetrate the brain [ 39 ]. By the same token, gain-of-function mutations at NaV1.7 are associated with paroxysmal extreme pain disorder and other debilitating conditions [ 39 ]. Other NaV channels, namely NaV1.8 and NaV1.9, appear to play a role in somatic and visceral pain syndromes [ 39 ].

The role of transient receptor potential cation channel subfamily vanilloid (TRPV) member 1 (TRPV1) has been described as signal integration of molecular transmission from the nociceptors, thus playing a role in acute pain [ 40 ]. In a rat model of incisional pain, dilute capsaicin (0.025 to 0.10%) administered perineurally or via local infiltration reduced guarding behaviors and heat hyperalgesia following plantar incision with few and mild effects on mechanical responses [ 41 ]. Capsaicin was found to reduce calcitonin gene-related peptide (CGRP) and isoelectric BF/protein gene product 9.5-immunoreactivity of the nociceptors, thus making them less sensitive to noxious stimuli [ 41 ]. TRPV1-expressing fibers may be more important to pain signaling than the TRPV1 receptor itself [ 40 ].

Reimaging acute pain management also means repurposing established agents. Allopurinol, a xanthine oxidase inhibitor used in gout treatment, was compared to placebo in a study of postoperative pain following abdominal hysterectomy [ 42 ]. Fifty-four patients were randomized to receive 300 mg oral allopurinol or placebo the night before surgery and one hour immediately before the operation. Allopurinol was shown to significantly reduce postoperative pain by 40% two hours after surgery; anxiety scores after surgery were similar between groups [ 42 ]. Thus, the purinergic system may be a potential new drug target for analgesics treating acute pain.

Acute inflammation

Inflammatory pain is a protective response that can aid and encourage the healing of injured tissue. In a healthy individual, inflammation is managed by a complex cascade of pro-inflammatory and anti-inflammatory chemical mediators that balance each other [ 43 ]. Among them, cytokines play a key role by initiating and regulating inflammatory responses [ 43 ]. Inflammation occurs in response to trauma or other insult and should resolve as the underlying injury and tissue heal; however, there are cases where inflammation does not resolve with healing and becomes chronic and maladaptive. Inflammation may persist because of infiltration of myeloid-derived suppressor cells, excessive and prolonged inflammatory response, inadequate production of anti-inflammatory mediators, and other causes [ 44 ]. Chronic inflammation is associated with numerous pathologic conditions, including cancer, obesity, rheumatoid arthritis, asthma, chronic obstructive pulmonary disorder, multiple sclerosis, Crohn’s disease, ulcerative colitis, and others [ 44 ].

Neuroinflammation is a cascade of inflammatory responses triggered by neuronal activity and is characterized by the release of pro-inflammatory mediators, activation of glia, and infiltration of immune cells into both peripheral and central nervous systems [ 45 ]. Neuroinflammation is more likely to progress to chronic pain than systemic inflammation [ 46 ]. Typically, acute pain is associated with an acute inflammatory response with transient central sensitization, and this inflammation resolves over time. If it fails to resolve, it can result in long-term or even permanent central sensitization and chronic painful syndromes. Thus, a better understanding of neuroinflammation in the context of acute pain is needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) are important agents for managing acute inflammatory pain because they inhibit cyclo-oxygenase-1 and/or -2 (COX-1 and -2) and prostaglandin production. Numerous NSAIDs are on the market, including selective COX-2 inhibitors (coxibs). Novel analgesics are in development. Among them are lipid mediators, such as resolvins, protectins, and lipoxygenase interaction products (lipoxins), which restore homeostasis to inflamed tissue.

There are specialized pro-resolving mediators that can aid in the clearance of tissue pathogens and debris around infectious inflammation [ 47 ]. For example, following spinal cord injury, anti-algesic lipid mediators are released to suppress inflammation. Their actions are mediated by GPCRs found on macrophages and glia [ 48 ]. Other novel agents for the control of inflammation include cannabinoids, which have been shown to produce antinociception in animals [ 49 ]. Humans have two cannabinoid receptors, known as CB-1 and CB-2, and the psychoactive effects of cannabis appear to be mediated entirely through CB-1. Both CB-1 and CB-2 appear to reduce inflammation [ 50 ]. However, the evidence for the use of cannabinoids for acute pain and inflammatory control remains mixed [ 51 ].

NSAIDs, particularly ibuprofen, diclofenac, and ketoprofen, are the most widely used analgesics for acute pain, but they have been associated with adverse events, such as gastrointestinal events or adverse cardiovascular events [ 52 ]. Long-term use of oral NSAIDs is not generally recommended [ 53 ]. Topical NSAIDs have provided good results in appropriate patients [ 45 ]. The short-term use of NSAIDs in appropriate patients may be helpful to manage acute pain.

Opioids can be effective pain relievers and are better suited for short courses than long-term use [ 45 ]. Pregabalin has been shown in preclinical trials to be effective against inflammatory pain and it is known to be effective in humans for treating neuropathic pain [ 45 ]. Corticosteroids may be used to address inflammatory pain and colchicine, which blocks IL-1β, may down-regulate multiple pathways for inflammatory pain [ 45 ].

Multimodal therapy uses a combination of agents with complementary mechanisms of action and often offers reduces opioid consumption without sacrificing analgesic benefits [ 45 , 54 ]. The ideal treatment for acute pain must first identify the cause of the pain and then based on an understanding of the underlying pain mechanism(s) and the molecular targets of various agents, arrive at a specific and precise analgesic regimen that is individualized to meet the needs of the patient [ 55 ].

Acute postoperative pain

Uncontrolled postoperative pain increases the risk of morbidity, dysfunction, decreased quality of life, impaired sleep, delayed recovery time, higher associated healthcare costs, and increased consumption of postoperative opioids [ 56 ]. Poorly controlled postsurgical pain can become chronic, resulting in persistent postsurgical pain (PPSP), which is far more challenging to treat [ 57 ]. In a study of 411 cognitively intact elderly patients undergoing surgery for hip fracture, higher pain scores at rest were significantly associated with longer hospital stays, physical therapy sessions, and delayed ambulation. At six months, those with higher pain scores at rest had significantly longer hospital stays, were more likely to miss physical therapy, and had lower locomotion scores both after surgery and at six months [ 58 ]. Postoperative pain at rest was associated with long-term functional impairment, although in this study it was not associated with residential care placement or six-month survival.

In a prospective survey of 625 elective surgery patients, patients were asked about pain prior to surgery, four days post-surgery, and again at six months [ 59 ]. Patients reporting high levels of pain four days after their operation (severe acute postoperative pain) and those whose surgeries lasted more than three hours were at significantly increased risk for increased pain, functional deficits, poor global recovery, and reduced quality of life at six months. There is a biopsychosocial aspect to this transition of acute to chronic pain because the fear of long-term consequences of surgery prior to the operation was associated with higher pain levels, poor global recovery, and worse quality of life after six months, whereas optimism prior to surgery was associated with improved recovery and better quality of life [ 59 ]. Yet biopsychosocial contexts for acute postoperative pain are not often considered in real-world clinical practice.

The type of surgery may also influence which patients develop PPSP. The incidence of PPSP is 30% to 50% for amputations and coronary artery bypass graft surgery; 30% to 40% for thoracotomy; 20% to 30% for breast surgery; and 10% for inguinal hernia or Cesarean section [ 57 ]. In a survey of 110 thoracotomy patients, 68% reported persistent pain three months after the operation, of whom 11% said pain levels >3 on a 0-10 scale and they reported significantly reduced function and vitality compared to those without pain [ 60 ]. PPSP is considered “severe” in 2% to 10% of these patients and often has a neuropathic component [ 57 ].

Since opioids are effective pain relievers, their short-term use to manage acute postoperative pain can benefit appropriate patients; current guidelines from the United States state opioids are to be used at the lowest effective dose for the shortest period of time [ 61 ]. There may be important considerations for patients who are currently taking opioids compared to those who do not take them at all. In a retrospective review of 6,364 patients who underwent unilateral total knee arthroplasty, it was found 24% were taking opioids prior to surgery, and of that group of opioid-experienced patients, 14% continued to take opioids 12 months after the procedure. Most patients in this study did not take opioids prior to the surgery and discontinued them within 12 months post-surgery. Of the opioid-naive patients who had not taken any opioids before surgery, only 3% were consuming opioid analgesics at 12 months. Thus, opioid-naïve patients were less likely to continue taking opioids than opioid-experienced patients. Furthermore, patients who took opioids 12 months following surgery were more likely to report greater pain at 12 months than those who did not continue taking opioids [ 62 ].

The differences between opioid-naïve and opioid-experienced surgical patients are telling. In a study of 574 patients undergoing either total knee or hip arthroplasty, 29.0% (n=167) were taking opioids on the day of their operation and experienced significantly greater pain at the surgical site, worse joint stiffness, more functional deficits, worse overall body pain, and significantly more symptoms of depression, anxiety, and catastrophizing compared to those who were not taking opioids prior to surgery [ 63 ]. Taking opioids before or after surgery exposed patients to the risk of prolonged opioid use, although, paradoxically, opioids still remain an important agent for the treatment of postoperative pain. While opioids are effective, they are also associated with adverse drug events which, in turn, were associated with higher costs and increased length of stay [ 64 ]. In a retrospective analysis of 592,127 surgical inpatients, opioids were associated with respiratory depression with rates ranging from 3% to 17% based on the type of surgery and incidences of nausea and vomiting ranging from 44% to 72% [ 65 ]. These complications could sometimes be associated with greater costs and longer hospital stays. Thus, the role of opioids in managing postoperative pain is coming under increasing scrutiny. 

It has been recommended that hospitals incorporate an acute pain service into their system to help better manage acute pain, particularly acute postsurgical pain. Despite greater awareness of PPSP and acute pain in general, the rates of PPSP have not decreased [ 66 ]. A general rule of thumb holds that about 10% of the surgical population will go on to have PPSP, which typically starts as acute pain and transitions into a chronic pain syndrome with a neuropathic component [ 2 , 45 ]. Such PPSP syndromes do not typically respond to opioid analgesia [ 67 ]. The neuropathic component of PPSP may pose challenges to treatment. In a systematic literature review, Haroutiunian and colleagues found that PPSP was likely to have a neuropathic component in 66% to 68% of breast cancer patients, 31% in patients undergoing groin hernia repair, and 6% after total hip or knee arthroplasty [ 68 ]. It is important for clinicians to recognize that PPSP can occur even after relatively minor surgical procedures, and it may develop in pediatric as well as adult or elderly patients. While only 2.2% of PPSP patients categorize their pain as severe, a neuropathic component may lead to more intense pain and greater dysfunction [ 69 , 70 ]. When diagnosing PPSP, it is important to rule out pre-existing painful conditions; postoperative complications, such as infection; and recurrence of the underlying disease or condition [ 71 ]. PPSP should also have lasted at least six months and be localized to the surgical field, innervation area of the nerve(s) in the surgical field, or the dermatome [ 72 ]. 

Patient factors may also contribute to acute pain. An observational study and survey of 100 patients who were diagnosed with post-traumatic and/or postsurgical neuropathic pain (mean pain levels 5.6 on a 0-10 scale) found that more severe pain was correlated with the number of comorbidities, and those with the most severe pain reported significantly more dysfunction, sleep problems, and depression compared to those with less-severe pain levels [ 73 ]. 

In a retrospective database study of 36,177 surgical patients (29,068 minor and 7,109 major surgery) who had filled a perioperative opioid prescription but had not taken opioids in the 12 months before the surgery, the rates of those with persistent opioid use were 5.9%, and 6.5% of minor and major surgery patients. In this study, persistent use was defined as refilling an opioid prescription between 90 and 180 days after surgery. The control group, who did not undergo surgery, had a much lower persistent opioid use rate of 0.4%. Some interesting patient risk factors for persistent opioid use emerged in this study: preoperative tobacco use, alcohol and/or substance use disorders, mood disorders, anxiety, and certain preoperative painful conditions, namely back pain, neck pain, arthritis, or centralized pain [ 74 ]. Since major surgery is likely to cause worse pain than minor surgery, but the prolonged use of opioids after surgery was similar for major and minor surgery patients, this suggests that protracted opioid use may be caused by reasons other than pain. This raises again the issue that patient factors and biopsychosocial considerations may be important for us to reframe acute pain and reimagine how it is treated. Genetic factors likely play an important role in terms of which surgical patients develop PPSP, but remain to be elucidated [ 75 ]. In addition to biopsychosocial factors, demographic information and clinical considerations relating to the type of surgery and underlying disease appear to play a part as well [ 76 ].

Conclusions

Elucidation of the physiopathology of acute pain has resulted in new findings, namely that acute pain (like chronic pain) is a biopsychosocial phenomenon that may be influenced by numerous patient-specific and treatment-specific factors. As acute pain is elucidated, emerging treatments for it including nonpharmacological methods should be investigated. Conditioned pain modulation may be a pain-regulating technique for acute pain and other approaches such as PNS are being used for acute pain. New agents such as allosteric modulators may revolutionize opioid analgesia by modulating the response of opioid receptors. Opioids are effective analgesics but may in some cases paradoxically be associated with worse or more prolonged pain. Most acute painful symptoms involve an inflammatory component, but the inflammatory response in acute pain syndromes differs from chronic inflammation such as occurs in neurodegenerative disorders. Reimagining acute pain management means considering pain in context, evaluating novel agents and nonpharmacologic treatments, and being more cognizant of the prevalence of untreated or under-treated acute pain. In some cases, acute pain can transition into chronic painful conditions which are difficult to treat and may lead to dysfunction and disability.

Acknowledgments

The authors are grateful to Mrs. JoAnn LeQuang for her support with the preparation of the manuscript. They also express their gratitude to the Paolo Procacci Foundation for the editorial support and to the Fondazione Internazionale Menarini for the organization of the convention.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

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Pain Management Research *

James d heckman , md, marc swiontkowski , md, jeffrey n katz , md, msc, elena losina , phd, andrew j schoenfeld , md, msc, nicholas a bedard , md, christopher m bono , md, james l carey , md, mph, brent graham , md, msc, frcsc, robert n hensinger , md, mark c gebhardt , md, william j mallon , md, michael j rossi , md, ms, elizabeth matzkin , md, michael s pinzur , md.

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Issue date 2020 Jun.

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ) which permits non-commercial use, reproduction and distribution of the work as published without adaptation or alteration, without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage ).

Over the past decade, increased awareness by the medical profession of the devastating consequences of opioid addiction has resulted in substantial efforts to limit the number of opioid prescriptions for both perioperative pain management and chronic pain. While these efforts have had some success, opioid misuse remains a crisis, which we in the orthopaedic community have a particular opportunity to address. It is the belief of the undersigned that progress depends on improved research methods and reporting to further the understanding of pain experience and response to management, with the end goal of identifying more effective, nonnarcotic pain control measures for our orthopaedic patients.

To further these efforts, JBJS, with support from an R-13 scientific meeting grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, conducted a Symposium on Pain Management Research in Newton, Massachusetts, on November 19, 2019. At this meeting, 10 experts in pain research along with 12 orthopaedic journal editors came together to present and discuss the latest findings on perioperative musculoskeletal pain management, define unmet clinical needs, and develop a set of guiding principles for the next phase of research in this arena. This endeavor came to fruition in a series of papers published as the JBJS Supplement on Pain Management Research as well as a summary list of Recommendations for Pain Management Research based on those papers and the meeting itself.

We hope that investigators will find the JBJS Supplement on Pain Management Research to be a useful guide when designing and reporting future studies. Again, we believe that strengthening the integrity of pain management research is key to winning the battle against the opioid crisis, which requires moving away from narcotics as a primary mode of pain relief while improving the pain experience of our patients.

Recommendations for Pain Management Research *

1. Definition: Define all terms (such as “new opioid prescrip- tion” or “long-term opioid use”) precisely, using criteria established by the Centers for Disease Control and Prevention (CDC) or a similar institution if possible. If a more established descriptor is not applicable to the database, explain why and clearly state the criteria for the definition used.

2. Quantification: Quantifying opioid use in morphine milligram equivalents (MMEs) enables comparisons within the literature. As >1 conversion factor is available, state how MMEs were calculated. The CDC provides a toolkit for calculating MMEs.

3. Population: As different groups experience pain differently, the study population (age, sex, socioeconomic, cultural) should be defined precisely. Research on sex-based differ- ences in pain experienced and response to opioids is needed.

4. Risk factors/predictors: Factors such as previous pain/opioid use, demographics, depression, catastrophizing, expectations, sleep disturbance, somatosensory function, physical activity, and coping ability should be studied as contributors to musculoskeletal pain and risk of opioid overuse.

5. The key measure should be better patient-related outcomes—including a positive experience that is free of complications and excessive pain—not just number of pills taken.

6. Distinguish among medications prescribed, obtained, and consumed. Be clear about the methods used to obtain these data and their limitations.

7. Pain relief using alternative strategies (nonsteroidal anti-inflammatory drugs [NSAIDs], ice, nerve growth factor inhibitors, psychological interventions), as opposed to elimi- nation of opioids, should be a goal. n

James D. Heckman, MD , Editor Emeritus, Marc Swiontkowski, MD , Editor-in-Chief, and Jeffrey N. Katz, MD, MSc, Elena Losina, PhD , and Andrew J. Schoenfeld, MD, MSc , Deputy Editors, The Journal of Bone & Joint Surgery; Nicholas A. Bedard, MD , Editorial Board, The Journal of Arthroplasty; Christopher M. Bono, MD , Editor-in-Chief, The Spine Journal; James L. Carey, MD, MPH , Associate Editor, American Journal of Sports Medicine; Brent Graham, MD, MSc, FRCSC , Editor-in-Chief, The Journal of Hand Surgery; Robert N. Hensinger, MD , Editor-in-Chief, Journal of Pediatric Orthopaedics; Mark C. Gebhardt, MD , Senior Editor, Clinical Orthopaedics and Related Research; William J. Mallon, MD , Editor-in-Chief, Journal of Shoulder and Elbow Surgery; Michael J. Rossi, MD, MS , Assistant Editor-in-Chief, and Elizabeth Matzkin, MD , Editorial Board, Arthroscopy: The Journal of Arthroscopic and Related Surgery; and Michael S. Pinzur, MD , Associate Editor, Foot & Ankle International

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Funding for the Pain Management Research Symposium was made possible (in part) by a grant (1R13AR076879-01) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. The Disclosure of Potential Conflicts of Interest form is provided with the online version of the article ( http://links.lww.com/JBJS/F816 ).

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIH.

OA: Copyright © 2020 The Authors. Published by The Journal of Bone and Joint Surgery , Incorporated. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

doi:10.2106/JBJS.20.00289

This editorial is also being published in The Journal of Bone and Joint Surgery, The Spine Journal, The Journal of Hand Surgery, Journal of Pediatric Orthopaedics, Journal of Shoulder and Elbow Surgery , and Arthroscopy : The Journal of Arthroscopic and Related Surgery . Michael Pinzur, MD, Assistant Editor, attended this symposium representing Foot & Ankle International .

These recommendations are based on presentations and discussions at the Pain Management Research Symposium held in Newton, Massachusetts, on November 19, 2019, as well as the articles in the Supplement on Pain Management Research (J Bone Joint Surg Am. 2020 May 21;102[Supplement 1]) authored by experts in pain research participating in that meeting.

Disclosure: Funding for this conference was made possible (in part) by a grant (1R13AR076879-01) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

Copyright © 2020 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

J Bone Joint Surg Am. 2020;00:1-1 d http://dx.doi.org/10.2106/JBJS.20.00291

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• Published: 18 January 2024

A systematic review and network meta-analysis of pharmaceutical interventions used to manage chronic pain

• Ashish Shetty 1 , 2 , 3   na1 ,
• Gayathri Delanerolle 4   na1 ,
• Heitor Cavalini 5   na1 ,
• Chunli Deng 6   na1 ,
• Xiaojie Yang 7 , 8 ,
• Amy Boyd 9 ,
• Tacson Fernandez 2 ,
• Peter Phiri 5 , 10 ,
• Arun Bhaskar 11 &
• Jian Qing Shi 5 , 6 , 7  

Scientific Reports volume  14 , Article number:  1621 ( 2024 ) Cite this article

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• Drug development
• Neuropathic pain

It is estimated 1.5 billion of the global population suffer from chronic pain with prevalence increasing with demographics including age. It is suggested long-term exposure to chronic could cause further health challenges reducing people’s quality of life. Therefore, it is imperative to use effective treatment options. We explored the current pharmaceutical treatments available for chronic pain management to better understand drug efficacy and pain reduction. A systematic methodology was developed and published in PROSPERO (CRD42021235384). Keywords of opioids, acute pain , pain management , chronic pain , opiods , NSAIDs , and analgesics were used across PubMed, Science direct, ProQuest, Web of science, Ovid Psych INFO, PROSPERO, EBSCOhost, MEDLINE, ClinicalTrials.gov and EMBASE. All randomised controlled clinical trials (RCTs), epidemiology and mixed-methods studies published in English between the 1st of January 1990 and 30th of April 2022 were included. A total of 119 studies were included. The data was synthesised using a tri-partied statistical methodology of a meta-analysis (24), pairwise meta-analysis (24) and network meta-analysis (34). Mean, median, standard deviation and confidence intervals for various pain assessments were used as the main outcomes for pre-treatment pain scores at baseline, post-treatment pain scores and pain score changes of each group. Our meta-analysis revealed the significant reduction in chronic pain scores of patients taking NSAID versus non-steroidal opioid drugs was comparative to patients given placebo under a random effects model. Pooled evidence also indicated significant drug efficiency with Botulinum Toxin Type-A (BTX-A) and Ketamine. Chronic pain is a public health problem that requires far more effective pharmaceutical interventions with minimal better side-effect profiles which will aid to develop better clinical guidelines. The importance of understanding ubiquity of pain by clinicians, policy makers, researchers and academic scholars is vital to prevent social determinant which aggravates issue.

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Introduction.

Chronic non-cancer pain conditions are prevalent, highly debilitating and have high cost implications to health and social care. These conditions affect patients, their families and society at large, impacting 20% of the global population 1 . The prevalence of pain conditions among females of all ages appears to be increasing 2 . Complexities around diagnosis and treatment of chronic pain conditions have meant that there is a paucity of standardised clinical guidelines that could potentially improve the clinical practice landscape, globally.

Convalescent periods for many chronically ill patients can be protracted and daunting. This may be especially true where pain medication has been used in the long term 3 . Long-term exposures to chronic pain coincide with mental health and wellbeing, exacerbating patient-reported outcomes such as sleep disturbances, depression, dependence and morbidities such as myalgia and fatigue 4 . Better understanding of long-term implications requires consideration of “life-course approaches” and at present, this could evolve further within pain medicine epidemiology 5 .

Increases in chronic pain conditions contributes to higher healthcare costs towards clinical management of patients and also reduced levels of productivity for employers 6 . This may be partly due to increases in opioid use within this population of patients, often reducing their capacity to conduct normal working hours. Current clinical guidelines recommend non-invasive pain management options as a first-line treatment among non-cancer patients in particular, although overdose, dependency and mortality due to opioid use has consistently increased over time 7 , 8 . It was reported that global opioid use has doubled between 2001 and 2003 to 2011 and 2013 to 7.35 billion daily doses per year 9 , 10 .

It is particularly important to develop evidence-based guidelines specific to each condition, with flexible pain medication use as a single regimen or a combination of treatments that could improve the overall quality of life of these patients 11 , 12 . The premise to increase the strength and frequency of pain medications is in general based on disease burden i.e., progression of symptoms and patients reported symptoms 4 .

We have designed the POP project as the initial step to conduct exploratory work on pharmaceutical management of chronic pain. With the rising need for comparative effectiveness research, increasingly more systematic reviews focus on evaluating the relative efficacy and acceptability of drugs and therapeutic interventions 3 , 13 . However, some of the interventions for long-term conditions are not available for clinical practice and there are several options with varying efficacy even within a specific class of interventions 14 .

We developed a wide systematic methodology and published this as a protocol with multiple research questions in the first instance in PROSPERO (CRD42021235384). Data from studies meeting the inclusion criteria were extracted and Pairwise Meta-Analysis with random and fixed effects models was carried out. Pooled mean difference (MD) together with 95% confidence intervals (CIs) are reported overall and for sub-groups. By combining the direct and indirect comparisons between different interventions, Network Meta-Analysis was conducted to explore the relative treatment effects among all the drugs included in our analysis.

The aims of the study was to explore the prevalence of treatments of effects in chronic pain based on pharmaceutical treatments.

Search strategy

The search strategy used key words of chronic pain , opioids , acute pain , pain management , opiods , NSAIDs, analgesics across multiple databases (PubMed, Science direct, ProQuest, Web of science, Ovid Psych INFO, PROSPERO, EBSCOhost, MEDLINE, ClinicalTrials.gov and EMBASE).

Eligibility criteria

All randomised controlled clinical trials (RCTs), epidemiology and mixed-methods studies reporting the use of pain medication for non-cancer chronic pain conditions published in English between the 1st January 1990 and 30st April 2022 were included. Opinions, commentaries and editorials were excluded (Fig. 1 ).

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only 15 .

Data extraction

Participants included in the study populations had chronic non-cancer pain conditions. All studies reporting drug efficacy were extracted by way of the interventions, measures of tool and numeric results. An extraction template specific to the objectives of the study was developed. Sub-studies were extracted from the same clinical trials with different duration periods.

Data was extracted by two investigators and any disputes for eligibility was discussed and agreed with the Chief Investigator of the study. All studies included within the analyses were independently reviewed.

Outcome measures

Outcomes were reported as mean, median, standard deviation and confidence intervals. Mean and Standard deviation (SD) were extracted as the main outcomes including pre-treatment pain scores at baseline, post-treatment pain scores and pain score changes of each group.

Multiple pain assessments for confirming a clinical diagnosis, severity and progression of chronic pain were identified. These include VAS (visual analogue scale, 0–10 or 0–100), NRS (11-point numeric rating scale, 0–10), BPI (Brief Pain Inventory interference scale, 0–10), MPQS (McGill Pain Questionnaire-Short Form (Sensory and Affective subscales, VAS intensity measure, 0–10), VRS (verbal rating scale, 0–10), NIH-CPSI (National Institutes of Health Chronic Prostatitis Symptom Index, pain scores, 0–21), PI (pain intensity on a 20-point scale, 0–20).

As most widely used tools for assessing pain such as VAS, NRS, VRS, use a 11-point numeric rating scale from 0 to 10, the following standardisation formula was used to unify all pain scores into the same scale:

As all outcomes of interest were continuous, the calculation based on pain scores was performed by using mean differences (MD) with a 95% confidence interval (CI) to report the effects between the group comparisons.

The exposures of interest were selected based on the key features of pharmacological management used to treat non-cancer chronic pain, including and not limited to a pain condition being the primary or the secondary condition. Neurological and psychological symptoms leading up to the use of pharmaceutical use within the included population were also considered.

Statistical analysis plan

A meta-analysis, pairwise meta-analysis (PMA) and Network meta-analysis (NMA) were used to compare all treatments used in managing non-cancer chronic pain. The fundamental difference between them is that PMA produced only one estimate of pooling effects from the selected pair of interventions, while the NMA produced multiple comparative estimates of pooling effects by connecting all alternative interventions 16 .

We incorporated direct and indirect treatment comparisons within the NMA providing greater statistical precision compared to a PMA. Rankings of a set of drugs or combined interventions for assessing chronic pain with respect to their efficacy was calculated based on the network models. Homogeneity and Consistency were tested to see if the assumptions in NMA were violated. The overall pharmaceutical efficacy of extracted studies was produced by pooling all treatment effects. PMA was also used on studies with the same drug as the treatment group to see the specific drug efficacy.

\({{\text{I}}}^{2}\) and p-value were commonly used to detect statistical heterogeneity. A value of \({{\text{I}}}^{2}\) larger than 50% with a much smaller p-value indicates strong heterogeneity. Correspondingly, \({{\text{I}}}^{2}\) less than 50% with a large p-value indicates fairly weak heterogeneity 17 . A random effects model was chosen when there was high heterogeneity, whereas a fixed effects model was used if weak or no heterogeneity was detected 18 . Due to the presence of high heterogeneity, subgroup analyses were carried out to identify the sources. To assess the robustness of the pooled results within the PMA, a sensitivity analysis was completed. Publication bias was evaluated with funnel plots and Egger tests. The statistical analyses were produced by R and packages were used to provide outputs in compliance with best practice and reporting guidelines 19 .

Of the 119 systematically included studies (Table 1 ) with 17,708 participants, 24 studies were used in the meta-analysis and 34 within the NMA to build a connected network.

Opioids (Table 2 ) were tested in 32 (26.89%) studies with 5518 (31.16%) participants, where Morphine , Oxycodone and Fentanyl were common. Lidocaine , Naloxone and Gabapentin were the most frequently tested non-opioid drugs for chronic pain. The most common pain among chronic pain patients were lower back pain, which was explored in 26 (21.85%) studies with a pooled sample of 4626 (26.12%) while 13 studies reported chronic back pain among 1068 (6.03%) participants. The following pain types are post-surgical pain and neuropathic pain with 19 (15.97%) and 10 (8.4%) studies involved to test the efficiency of NSAID drugs on patients.

Meta-analysis of mean difference of pain scores were applied to 24 studies with a sample of 2546 participants, producing a pooled mean difference (MD) of – 0.89 (95% CI [− 1·31, − 0·47]). There was a significant difference between chronic pain scores of patients taking NSAIDs compared to a placebo. Averagely, 0.89 point (0–10 scale) of pain reduction was observed based on the random effects model. A significant statistical drug efficiency was observed with BTX-A and Ketamine. A negative pooled mean difference was determined between BTX-A and Ketamine versus a placebo with a pain reduction of 0.98–1.26 based on a − 10 scale, respectively. Similar statistical results were not observed with other drugs in comparison to a placebo.

Within the common comparator as a “ placebo ”, the connected network included 34 studies, 52 pairwise comparisons, 32 interventions and 29 study designs. Gabapentin had a significant mean difference equalling to – 1.49 (95% CI [− 2 ⋅ 76, − 0 ⋅ 23], p-value < 0.05). Most interventions had a negative mean difference compared to a placebo , but a 95% CI covering 0 indicated insignificant effects for reducing pain. The results within the network were more conservative with the combination of direct and indirect evidence indicating most pharmaceutical interventions selected might have benefited from the “ placebo effect ”.

Pairwise meta-analysis (PMA)

The PMA included 24 studies with pairwise comparisons between drugs and a placebo. The experimental and control group comprised of "Amitriptyline", "BTX-A”, “Gabapentin", "Ketamine", "Lidocaine", "Morphine", "Naloxone" and a placebo, respectively. A single study reported "Fentanyl", "Ningmitai", "THC", and "Oxycodone".

PMA for baseline pain score

The PMA was used to test baseline pain score differences between the experimental and control group in 18 studies which comprised of a total sample of 1691 participants. The experimental and control groups comprised of 837 and 854 participants, respectively, with a pooled mean difference (MD) of – 0.02 (95% CI [− 0.13, 0.08]). The 95% CI was 0 and therefore, no statistically significant difference between baseline pain scores of two groups (Fig.  2 ). A weak statistical heterogeneity of 15% of \({I}^{2}\) (p = 0.26) was determined. This combined with the statistical insignificance indicates the randomisation of was completed accurately and that it is scientifically justifiable to use the post-treatment pain scores directly as the outcomes to evaluate treatment effects.

Forest plot for the baseline pain scores of experimental group and control group across 18 studies.

PMA for drug efficacy between NSAID compared to a placebo

This PMA included 24 studies (Fig.  3 ) with 2418 participants, with a MD of − 0.89 (95% CI [− 1.31, − 0.47]). The experimental and control group comprised of 1219 and 1199, respectively. A significant statistical heterogeneity of 92% of \({I}^{2}\) (p-value < 0.01) was identified. Mean difference (MD) was calculated to assess if there is statistically significant difference of post-treatment pain scores between experimental group and control group. The 95% CI was less than 0 which indicated a significant treatment effect with a reduction in pain by 0.89-point (0–10 scale) compared to those who were given a placebo.

Forest plot for the pain scores of experimental group and control group across 24 studies testing all NSAID drugs (including some unnamed Opioids drugs).

Meta-analyses

A statistically low heterogeneity of 0% of \({I}^{2}\) (p-value > 0.5) was identified among studies with BTX-A, Ketamine and Naloxone (Fig.  4 b,d). BTX-A (Fig.  4 b) and Ketamine (Fig.  4 d) indicated statistically significant drug efficacy of – 1.07 [−1.51, − 0.64] and − 1.26 [− 1.85, − 0.68], respectively. The treatment efficiency compared to the placebo had a 1 point pain reduction within a 0–10 evaluation scale. Ketamine demonstrated optimal efficacy with a 1·26 point pain reduction on average.

( a ) Forest plot for drug efficiency of Amitriptyline. ( b ) Forest plot for drug efficiency of BTX-A. ( c ) Forest plot for drug efficiency of Gabapentin. ( d ) Forest plot for drug efficiency of Ketamine. ( e ) Forest plot for drug efficiency of Lidocaine. ( f ) Forest plot for drug efficiency of Morphine. ( g ) Forest plot for drug efficiency of Naloxone.

The PMA for BTX-A (Fig.  4 b) and Naloxone (Fig.  4 g) showed a low heterogeneity as the data was pooled from a single study.

Studies on Amitriptyline, Gabapentin, Lidocaine and Morphine had a high heterogeneity and a statistically insignificant drug efficacy (Fig.  4 a,c,e,f). The mean difference of 95% CI was 0 indicating an insignificant treatment difference between the drugs and placebo based on the random effects model.

Opioids drugs

A meta-analysis was conducted with 4 studies (Fig.  5 ). A pooled MD of – 0.65 and a 95% CI [− 1.67, 0.37] was determined indicating an insignificant treatment effect of opioids drugs compared to a placebo. A statistically significant heterogeneity of 92% of \({I}^{2}\) (p-value < 0·01) was identified.

Forest plot for drug efficiency of Opioids drugs*.

Network meta-analysis (NMA)

A NMA (Fig.  6 ) was completed for 34 studies. The nodes correspond to each intervention included within the network where the interventions with direct comparisons are linked with a line. The thickness of lines corresponds to the number of trials evaluating the comparison. A connected network was built based on the placebo which was mostly Tolterodine based on the original studies. The evaluations between interventions were supported by direct comparison and indirect comparison.

Network plot where Placebo was the reference group with 34 studies and 32 interventions.

In the network with the placebo as the reference group, Gabapentin (Fig.  7 ) comprised of a MD equaling to – 1.49 (95% CI [− 2.76, − 0.23], p-value < 0.05) indicating a significant effect on reducing chronic pain and direct comparisons were made using 4 studies (Fig.  8 a). The pooled MD of Botulinum and Ketamine were −1.06 and – 1.24, respectively. These were similar to the results in the PWA, but their 95% CI was 0 therefore showed insignificant effect on pain reduction compared to a placebo. Most combined interventions had a negative MD compared to a placebo with a 95% CI of 0 indicated statistically insignificant results for reducing pain.

Forest plot for intervention efficiency compared to Placebo in NMA.

Forest plot for intervention efficiency compared to Placebo in NMA with detailed direct and indirect comparisons.

Imipramine , Diosimin , Desipramine , Clobazam , Piroxicam and Tiagabine had not been directly compared to a placebo based on the identified data therefore the comparative treatment effected between them and a placebo was not possible to complete.

Subgroup analysis

A subgroup analyses was conducted for 24 studies within the meta-analysis to explore the sources of heterogeneity and unbiased estimation based on age, pain type, period and geographical location (Fig.  9 ). The sub-group analysis for pain type, time period and geographical location can be found in the Supplementary file whilst average age is shown below.

Forest plot for the mean difference of pain scores between experimental group and control group across different mean age of participants.

Subgroup analysis for pain core difference based on different age groups

It showed that the heterogeneity among studies with participants who were older than 50 years old had changed with decreased I 2 ( I 2  = 48% for “51–60”, I 2  = 68% for “61–71”). A common effects model was chosen for subgroup “51–60”, which produced a higher estimation of pain reduction with a mean difference of – 1.46 (95% CI [− 1.74, − 1.18]). Based on the high heterogeneity ( I 2  > 50%), random effects models were built for other subgroups. The group with participants younger than 40 years older obtained a significant drug efficiency (MD − 1·05, 95% CI [− 1.85, − 0.24]). The pooled drug effects (Fig.  9 ) in the 41–50 and 61–71 years of age groups were much lower than the overall treatment effect of NSAID drugs identified in the PMA. The 95% CI of 0 indicated statistically ineffective compared to the placebo. The random effects models showed the decrease of heterogeneity indicating that age may be a source of heterogeneity.

Sensitivity analysis

The sensitivity analysis was conducted (Fig.  10 ) for the PMA where some studies influenced the pooled results compared to the overall estimation (− 0.89). To test this theory, study number 71 and 100 were omitted and the pooled results were much lower, − 0.82 and – 0.79, respectively. Studies with Amitriptyline and Gabapentin produced unstable treatment results, and the absence of these showed an overestimation (study 81, 45) or underestimates (study 71, 100). Collectively, the high heterogeneity ( I 2  = 92% p-value < 0.01) was stable and a robust treatment effect with negative mean differences and a significant 95% CI remained. Therefore, the pooled treatment effects identified was credible.

Forest plot for sensitivity analysis with studies in MA.

Publication bias

The funnel plots (Fig.  11 ) within the PMA indicated symmetry. Although several studies were not within the remit of the funnel, the Egger’s test showed a p value (0.22) larger than 0.05 which indicated the lack of small-study effects (Table 3 ).

Funnel plot for studies used in PMA.

We identified opioids and non-opioids were the two primary classes of pharmacological interventions in chronic pain management. Opioids are widely used in the management of cancer pain and non-cancer associated pain 20 , 21 . The long-term use of opioids in the management of chronic non-malignant pain has come under scrutiny more recently and is now recommended only if benefits of initiating treatment would significantly outweigh the potential risks, and possibly as an adjunct to the primary intervention 22 , 23 . Our study has shown that judicious use of non-opioid medications along with other treatment modalities could provide better outcomes in managing chronic pain thereby removing long-term side-effects observed during opioid therapy. With cancer patients increasingly being cured or achieving long term remission, prolonged use of opioids could result in aberrant behaviour and dependence. Awareness of an opioid crisis globally has prompted clinicians to exercise caution in their prescription habits, but the WHO supports the use of opioids including Fentanyl and Methadone as an essential class of medication for the management of cancer pain 24 , 25 .

The meta-analysis of baseline pain scores lacked statistical significance between experimental and control groups. The significant reduction in chronic pain scores of patients taking NSAID versus non-steroidal opioid drugs compared to patients given placebo under a random effects model. The presence of a significant drug efficiency with BTX-A and Ketamine is interesting although the pooled results of other drugs and interventions had statistically insignificant results with a 95% CI of 0. The pooled evidence indicated Ketamine showed the highest pain reduction (1.26) followed by BTX-A (0.98). Studies testing on other drugs including Amitriptyline, Gabapentin, Morphine and Lidocaine had a high heterogeneity and insignificant drug efficiency. Overall, evidence from the PMA showed a strong efficacy within the NSAIDs group with managing pain which were remarkably narrowed when exclusive trials with low risk of bias were included 26 , 27 , 28 .

In this study, a pairwise meta-analysis and NMA consolidating the evidence of 46 studies was carried out, with the former comparing several different opioids. Morphine has traditionally been used for the management of moderate to severe chronic pain 29 . Despite morphine being a potent analgesic [MD 0.01 (95% CI [− 1.18, 1.21], newer opioids are now being employed owing to their superior safety profile. Oxycodone and Fentanyl appear to be popular due to better availability and vast clinical experience including the well accepted effectiveness demonstrated, as per patient and clinically reported outcomes. Our results are aligned to these trends where the effectiveness is shown to include a MD 1.77 (95% CI [− 2.11, − 1.43]) for Oxycodone and a MD of − 0.90 (95% CI [− 2.03, 0.23])] for Fentanyl (32). However, untoward gastrointestinal effects (constipation, nausea, and vomiting) still remain a major concern with opioid use and are often responsible for discontinuation of treatment 30 , 31 . Recent evidence favours the use of a combination of oxycodone and naloxone in patients with chronic pain (after ensuring that there is no cause for porto-systemic anastomosis), to offer an improved bowel function without any effective change in analgesia 32 . The concerns of developing tolerance, opioid-induced hyperalgesia, aberrant behaviour and dependence with opioids is a pragmatic reason to develop effective alternative treatment modalities especially for vulnerable individuals. In pairwise comparison, we observed Ketamine to be superior to other pharmacological interventions with a mean difference MD − 1.26 (95% CI [− 1.85, − 0.68]).

There are several guidelines recommending the use of Pregabalin, Gabapentin, Duloxetine, and Amitriptyline as first line drugs in the management of neuropathic pain 33 , 34 , 35 . However, the use of gabapentinoids is being challenged as it lacks favourable robust evidence for efficacy against pain syndromes other than fibromyalgia, post herpetic neuralgia and diabetic neuropathy, and many clinicians have also highlighted the potential for misuse and developing dependence 36 , 37 , 38 . The use of BTX-A, Ketamine, Ningmitai and THC for the management of various chronic pain conditions is popular and well established 39 , 40 , 41 , 42 , 43 and our study shows the effective use of these as analgesics when compared to placebo. There is evidence to support the efficacy of BTX-A for the management of neuropathic pain although the sample sizes used in the studies were small and therefore the real-world applicability remains limited 29 . BTX-A is also used in management of myofascial pains 44 , 45 although further evidence on the efficacy and tolerability within all populations, especially those with existing co-morbidities needs to be evaluated. Ketamine was found to be beneficial in managing some neuropathic pains 46 and as an infusion the rates of serious adverse effects were found to be similar to placebo 47 , 48 . Further studies are required to gather evidence to better understand its psychedelic effects and its role in the management of PTSD, anxiety and depression. A renewed use of magnesium in managing chronic pain has been demonstrated in some literature 49 . Our results indicate similar evidence in the use of magnesium, but will require further research to determine the efficacy, safety and effectiveness in managing short, medium and long-term pain.

The NMA provided more reliable results with direct and indirect comparisons between different drugs under different study designs. However, only a small number of multi-arm trials were eligible and the distribution of trials studying different drugs was uneven. It resulted in the lack of direct evidence of certain drugs and their relative efficacy in the network was unstable due to excessive reliance on indirect comparisons. Therefore, well designed and robust clinical trials should be conducted to verify the efficacy of pharmaceutical interventions used in chronic pain management.

To the best of our knowledge, this is the first pairwise MA and NMA reporting the synthesis of the prevalence of the efficacy of pharmacological treatments used in the management of chronic pain with a large sample size of 17,708 participants. Management of long-term chronic pain needs to be prioritised for several reasons including humanitarian, the strain on the healthcare systems and the impact on the economy due to loss of productivity. The use of pharmaceutical agents in the long-term management of chronic pain has been debated for several decades, yet there has not been a consensus on this matter. This study supports the importance of generating better evidence by way of robust clinical trials, the need for drafting clinical guidelines that is pragmatic, practical as well as clinically significant and the use of better data-connectivity methods to improve clinical practice in the real-world.

Data availability

The authors will consider sharing the dataset gathered upon receipt of reasonable requests.

Code availability

The authors will consider sharing the novel code created upon receipt of reasonable requests.

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Acknowledgements

Dr Anish Thillainathan involved in formatting process.

University College London Hospitals NHS Foundation Trust.

Author information

These authors contributed equally: Ash Shetty, Gayathri Delanerolle, Heitor Cavalini and Chunli Deng.

Authors and Affiliations

University College London Hospitals NHS Foundation Trust, London, UK

• Ashish Shetty

University College London, 235, Euston Road, London, NW1 2BU, UK

Ashish Shetty & Tacson Fernandez

Pain Medicine, Cleveland Clinic London, London, United Kingdom

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, OX3 7JX, UK

• Gayathri Delanerolle

Southern Health NHS Foundation Trust, Southampton, SO40 2RZ, UK

Heitor Cavalini, Peter Phiri & Jian Qing Shi

Southern University of Science and Technology, Shenzhen, 518055, China

Chunli Deng & Jian Qing Shi

School of Statistics and Mathematics, Yunnan University of Finance and Economics, Kunming, China

Xiaojie Yang & Jian Qing Shi

National Centre for Applied Mathematics Shenzhen, Shenzhen, China

Xiaojie Yang

University of Oxford, Oxford, UK

Psychology Department, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK

Peter Phiri

Imperial College Healthcare NHS Trust, London, UK

Arun Bhaskar

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Contributions

A.S. and G.D. developed the study protocol and embedded this within the POP project. G.D. and J.Q.S. designed and completed the study analysis. The data extraction was completed by H.C. and C.D. All authors critically appraised and commented on previous versions of the manuscript. All authors read and approved the final manuscript. All authors consented to publish this manuscript.

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Correspondence to Ashish Shetty .

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Competing interests.

AS has received funding from Medtronic and Nevro Corp USA. PP has received research grants from Novo Nordisk, Queen Mary University of London, John Wiley & Sons, Otsuka, outside the submitted work. AB has received  speaker fees and has been an advisory board member from Pfizer, Vectura-Fertin and Reckitt. All other authors report no conflict of interest. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute for Health Research, the Department of Health and Social Care or the Academic institutions.

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Shetty, A., Delanerolle, G., Cavalini, H. et al. A systematic review and network meta-analysis of pharmaceutical interventions used to manage chronic pain. Sci Rep 14 , 1621 (2024). https://doi.org/10.1038/s41598-023-49761-3

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Received : 19 September 2023

Accepted : 12 December 2023

Published : 18 January 2024

DOI : https://doi.org/10.1038/s41598-023-49761-3

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