Abstract
Background: Pain management is an evolving area of expertise in Qatar. Gaps in knowledge, inadequate training for physicians and nurses, and the absence of policies/guidelines are the main barriers to effective pain management in Qatar. In addition, the use of certain pain medication, especially opioids, is highly regulated, limiting their availability in outpatient pain management. These factors are responsible for the undertreatment of pain in Qatar. This study aimed to standardize evidence-based local recommendations for pharmacological treatment of pain in Qatar.
Methods: An expert panel of physicians from different disciplines, with experience in diagnosis and treatment of the three pain types (i.e., acute, chronic, and neuropathic), was convened for two face-to-face meetings in Doha, Qatar, on November 29, 2019, and on February 22, 2020, with subsequent virtual meetings. A literature search was performed on Medline and Google Scholar databases from inception till December 2019, and all relevant articles were selected. Based on these articles and repeated feedback from the authors, the final pain treatment protocols were developed.Results: Recommendations for the treatment of acute pain, based on pain severity, followed three approaches: acetaminophen/paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and moderate pain and referral to a pain specialist for severe pain. Acetaminophen/paracetamol or NSAIDs is recommended for chronic pain, and the use of opioids was strongly discouraged because of its long-term side effects. For neuropathic pain, tricyclic antidepressants or gabapentin or pregabalin or serotonin-norepinephrine reuptake inhibitors were recommended first-line agents. Non-responders must be referred to neurologists or a pain specialist.
Conclusion: The expert panel provides recommendations for the management of acute, chronic, and neuropathic pain based on international guidelines adapted to local practice and treatment availability in Qatar. More importantly, the panel has recommended taking extreme caution in the use of opioids for long-term management of chronic pain and to refer the patient to a pain specialist clinician as required.
Keywords: acute pain, analgesics, chronic pain, neuropathic pain, pain management
Introduction
Pain is often classified as the “fifth vital sign”; managing pain is key to improving the quality of life (QoL) of patients.1 The International Association for the Study of Pain task force, based on recent advances, recommended revising the definition of pain to “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage.”2 Pain has various classifications depending on its anatomic, etiologic, chronicity (duration), intensity, and pathophysiological characteristics.3
Worldwide, acute pain is one of the most common causes for patients to seek medical attention at the emergency department (ED).4 Lower back pain (LBP) is the leading cause of activity limitation and absence from work throughout the world. In the Global Burden of Disease 2017 study, years lived with disability (YLDs) because of LBP was 64.9 million with a point prevalence of 7.5%, accounting for 577 million people.5 In North Africa and the Middle East, the prevalence of LBP in 2017 was approximately 9.9% and ranked ninth among the 21 regions.5
In 2013, a cross-sectional survey on the epidemiology of LBP in the primary healthcare setting was conducted in Qatar and reported an overall LBP prevalence of approximately 59.2% in a sample of 2180 subjects.6 The prevalence of LBP in Qatar was higher than that in developed countries, such as Canada, United Kingdom, and Sweden.6
Occupation-related factors are key causal factors for LBP. The estimated prevalence of LBP among nurses in a tertiary care setting in Hamad General Hospital, Doha, Qatar, in 2015 was approximately 26.8%, with 34.3% of overall respondents requiring medical treatment for LBP.7
Migraine-related pain is another important cause of disability worldwide, requiring greater research resource allocation and attention in health policy debates. Worldwide, approximately 1.04 billion individuals may have experienced a migraine in 2016, leading to 45.1 million YLDs globally. In North Africa and the Middle East, approximately 93.4 million individuals may have experienced migraines in 2016, with 0.39 million individuals reporting migraine during the same period in Qatar.8
In general, challenges in pain management lie at the level of patients (i.e., culture, experience, education, and health condition), healthcare professionals, and the healthcare system. Challenges to effective pain management are multifold and stem mainly from the undertreatment and practice variations of pain, known as “oligoanalgesia.”9, 10 Some of the other key challenges in pain management are the inability to assess the initial pain, non-availability of pain management guidelines, and failure to acknowledge and document pain.10 One of the important factors adding up to the challenges in pain management is misuse and abuse of opioids to unacceptable levels.11
The dynamic nature of pain and its intensity highlight the importance of “stratified care”–a targeted approach for treating pain according to the risk category (i.e., low, medium, or high risk of poor outcomes) of patients.12 In the Middle East, including Qatar, pain management is an evolving area of expertise, and undertreatment is related to the stigma associated with the use of pain medications, especially the use of opioids.13 Knowledge gap and lack of skills by physicians and nurses and absence of policies/guidelines hinder effective pain management. In 2011, approximately 69% of the physicians in Qatar reported that they had not received any formal pain management training.14 Furthermore, cultural differences regarding pain exist in Qatar, as it is a cosmopolitan country with different coexisting communities. Similarly, physicians practicing in Qatar come from different communities and received training from varying educational systems.
Under these circumstances, treatment guidelines can aid in evidence-based decision-making. Guidelines have been established for the pharmacological treatment of acute pain and peripheral neuropathic pain in the Middle East.13, 15 However, there is an urgent need to develop standardized local guidelines, applying similar methodology for different types of pain including acute, chronic, and neuropathic pain, in Qatar. To address this unmet need, an expert forum was constituted to provide pharmacological treatment recommendations specific to Qatar, including the best practices from existing international guidelines.
Methods
An expert panel of physicians (Qatar Pain Expert forum, n = 15) from different disciplines (such as emergency medicine specialists, anesthesiologists, chronic pain specialist, stroke specialist, trauma and orthopedic surgeons, neurologists, and pharmacy specialists) with clinical and research experience in diagnosis and treatment of acute, chronic, and neuropathic pain was convened in Doha, Qatar, on November 29, 2019, and subsequently, on February 22, 2020, followed by virtual meetings. The experts were affiliated to Hamad Medical Corporation, the primary healthcare body in Qatar, Weill Cornell Medicine in Qatar, and Qatar University. A literature search for relevant publications was performed on the databases of Medline (PubMed) and Google Scholar from their inception till December 2019. The following key terms were used: [acute pain or perioperative pain AND management AND guideline OR protocol], [chronic pain AND management AND guideline OR protocol], and [neuropathic pain AND management AND guideline OR protocol]. “English language” and “Humans” were the applied limits. The relevant literature of 460 retrieved articles, which consisted of meta-analyses, systematic reviews, and evidence-based guidelines on the treatment, was reviewed by the authors in consultation with the expert panel to arrive at treatment protocols for acute, chronic, and neuropathic pain. Based on the experts’ comments on the identified literature, a preliminary draft document was prepared and circulated among the authors for further review. The document was revised multiple times according to the authors’ edits and feedback, and a final pharmacological treatment protocol for pain was achieved.
Expert recommendations for clinical management of pain in Qatar
Acute pain management in ED
Acute pain is a neurophysiological response to noxious injury lasting less than 3 months.16 Common examples of acute pain include postoperative pain, fractured bones, appendicitis, and soft tissue injury. Acute LBP is one of the common reasons for ED visits.
Evaluation of pain
The visual analog scale (VAS) and numeric pain rating scale (NRS) are commonly used for the assessment of pain intensity. A four-point verbal categorical rating scale (VRS) is also used, but the VAS and NRS are considered superior.17 However, consensus-based recommendations of an expert panel for the pharmacological treatment of acute pain in the Middle East concluded that both the NRS and VRS are more useful than the VAS in the general practice setting and that patient education is important to ensure accurate measurement.13
Pharmacological treatment
After careful evaluation, an effective pain management plan should be drawn by each ED to establish a diagnosis with measurable outcomes that focus on improving QoL, functionality, and activities of daily living.18 Emphasis should be on an individualized, patient-centered approach for the diagnosis and treatment of pain. Treatment of pain in the ED has no single standard of care.19 Many analgesic agents have varied physiological mechanisms and therefore chosen based on pain severity. The algorithm for the initial management of undifferentiated pain in the ED is illustrated in Figure 1 adapted from expert panel consensus recommendations for the pharmacological treatment of acute pain in the Middle East.13
Figure 1.
Initial management of undifferentiated pain in the emergency department–evidence-based clinical algorithm. ED, emergency department; IM, intramuscular; IV, intravenous; NRS, numerical rating scale; NSAIDs, nonsteroidal anti-inflammatory drugs; VRS, verbal rating scale.
Acetaminophen (paracetamol)
Acetaminophen is a widely used over-the-counter drug owing to its antipyretic and analgesic effect. Although its detailed mechanism of action is yet to be completely understood, it is likely to act by inhibiting cyclooxygenase (COX) enzymes through the metabolism of the peroxidase function of these isoenzymes. It also acts through serotonergic, opioid, nitric oxide, and cannabinoid pathways.20 It is highly selective and has an additive effect; however, it has no known synergistic effect when combined with other nonsteroidal anti-inflammatory drugs (NSAIDs). Acetaminophen available in both oral and intravenous (IV) formulations is approved up to the dose of ≤ 4 g/day owing to its hepatotoxicity.21 Acetaminophen has demonstrated a similar analgesic effect as do NSAIDs in patients who presented to the ED for acute pain.22-26 Sufficient evidence confirms the IV use of acetaminophen in hospitalized patients for treating pain with opioid-sparing effects.27-32 Moreover, many randomized controlled trials have shown that IV administration of acetaminophen has significantly lesser side effects than morphine in patients presenting with acute renal colic to the ED.33-36 A pooled analysis of 23 studies involving over 2000 patients aged < 18 years revealed that acetaminophen had lesser adverse events (AEs) than opioids.37
Nsaid
NSAIDs are agents that act by inhibition of COX enzymes and are proposed as the first-line drugs for mild-to-moderate pain. NSAIDs have known AEs such as gastrointestinal (GI) hemorrhage and peptic ulcers because of their effect on COX1 enzymes.11 Moreover, they are contraindicated in elderly patients and in patients with peptic ulcers, hypertension, renal disease or impairment, or hepatic impairment.38 NSAIDs should also be avoided in patients with a history of myocardial infarction, transient ischemic attack, stroke, or inflammatory bowel diseases such as Crohn's disease or ulcerative colitis.39, 40 Given these AEs, next-generation selective COX2 inhibitors were introduced with lower GI side effects. However, these agents are shown to have increased the risk of cardiovascular effects.11
In general, NSAIDs have been shown to be more effective than opioids but with no additional benefits when combined with opioids/or muscle relaxants in acute pain settings.41, 42 NSAIDs were found to have comparable efficacy with opioids and paracetamol in relieving acute pain at 30 minutes with lesser incidence of vomiting and requirement of rescue analgesia in treating acute renal colic pain.43 A double-blind, randomized controlled trial in Qatar found that intramuscular (IM) administration of diclofenac offers significantly more effective pain relief (odds ratio 1.35, 95% confidence interval [CI] 1.05–1.73, p = 0.0187) than does IV administration of morphine in patients presenting with renal colic pain to the ED. However, IM use of diclofenac and IV administration of paracetamol have comparable efficacy in relieving pain.44 Another prospective, randomized controlled trial in Qatar found that more patients receiving IM administration of diclofenac achieved a 50% reduction in pain within 30 minutes compared with oral intake of diclofenac (99.3% vs. 86.7%, p < 0.001). The authors, however, opted for oral over IM administration of diclofenac in patients presenting with acute musculoskeletal injuries to the ED.45
NSAIDs at equipotent doses had shown similar analgesic effects. In a prospective, double-blind study, ketorolac, diclofenac, and etoricoxib have shown similar efficacy and a significant reduction in acute pain caused by ankle fracture over 24 hours from baseline.46 Moreover, two studies have reported similar pain relief with parenteral use of ketorolac and oral intake of ibuprofen in acute pain settings.47, 48 Ketorolac was found to be non-inferior to naproxen for the reduction of mild-to-moderate LBP but provided a faster pain relief than did naproxen (24.2% vs 6.5%, p = 0.049).49 In the ED setting, IV administration of ketorolac at doses of 10, 15, and 30 mg has shown similar analgesic effects, proving that the 10 mg dose is the ceiling dose; however, 90% of patients received ketorolac above the ceiling dose in the ED settings.50 Additionally, IV administration of parecoxib sodium 40 mg was shown as an analgesic alternative to morphine sulfate 0.1 mg/kg in acute traumatic pain in the ED settings.51 A meta-analysis of seven randomized controlled trials revealed that a single IV or IM dose of parecoxib 20 mg or 40 mg in acute postoperative pain provided effective analgesia in 50%–60% of patients compared with approximately 15% with placebo.52 Topical NSAIDs are also used for chronic musculoskeletal pain in adults.53-55
Weak opioids
Tramadol
Tramadol is considered a weak opioid analgesic. It has two independent mechanisms to produce analgesic effects: the opioid mechanism (binds to the μ-opioid receptor) and the nonopioid mechanism (inhibits the reuptake of serotonin and norepinephrine). Supporting pieces of evidence present the use of tramadol alone or in combination with other analgesics in acute pain care.56-62 Although tramadol has an action on the opioid receptor, several clinical trials have shown that tramadol has fewer opioid side effects, including drug dependency, than do opioids.63-73
Codeine
Codeine is a weak opioid, as it has a 200-fold weaker affinity to μ-opioid receptor than morphine. Approximately 80% of the codeine administered is metabolized to codeine-6-glucuronide, which contributes to the analgesic effect. Codeine is available in combination with paracetamol.74
Strong opioids
Opioids are effective in the management of pain but have several limitations. Opioid analgesics are associated with an increased risk of respiratory depression, sedation, and addiction. A morbidity and mortality report released by the Center of Disease Control (CDC) showed that opioid-naïve patients who received opioids were more likely to have chronic opioid use with each additional day of medication use, starting with the third day, with the sharpest rise in chronic opioid use after the fifth and 31st day of therapy. Hence, the CDC recommends, “discussion with patients about the long-term use of opioids to manage pain should occur early in the opioid prescribing process.”75
The usage of opioids had increased sharply between 1990 and 2010.76 However, restrictions exist on access to opioids due to regulatory obstacles and concerns about misuse.77
Sufficient evidence has shown effective pain relief with both oral and parenteral use of strong opioids in patients with acute severe pain. However, studies have shown an increased risk of AEs, especially opioid dependency.8, 18, 78-87 Hence, the use of strong opioids should be restricted, and patients referred to a pain specialist for interventional modalities of pain management.
Experts recommendations for chronic pain treatment
Pain that lasts longer than the usual course (more than 3–6 months) of an acute injury or disease is called chronic pain.88, 89 Chronic pain has several pathophysiological causes.90
The effect of chronic pain is multifold, such as negative influence on QoL, depression, anxiety, disrupted daily routine, reduced social activity, disability, sleep disturbances, and increased healthcare cost.91 Often, chronic pain results from an unrelieved acute pain, e.g., LBP. Patients with chronic non-specific LBP should be referred to a specialist as the treatment might include opioids.
Evaluation of chronic pain
The PainDETECT, Douleur Neuropathique en four Questions, and Leeds Assessment of Neuropathic Symptoms and Signs are some of the validated questionnaires used to prompt clinicians for the assessment of chronic pain.92
Pharmacological treatment
Nsaids
Nonopioid medications are the preferred drugs for treating chronic pain (Table 1).93,94 NSAIDs are the first-line agents for mild-to-moderate pain and form the first step of the analgesic ladder in the treatment of chronic pain.19, 95 NSAIDs have shown modest benefits and a tolerable safety profile for the treatment of chronic back pain.96-98 However, a long-term use of NSAIDs, such as diclofenac, ibuprofen, and COX2 inhibitors, caused an increased risk of death from myocardial infarction and coronary heart disease (diclofenac, risk ratio [RR] 1.70, p = 0.0032; ibuprofen, RR 2.22, p = 0.0253; COX2 inhibitors, RR 1.76, p = 0.0001) but not naproxen (RR 0.84, 95% CI 0.52–1.35) compared with placebo.99
Table 1.
Guidelines for oral use of NSAIDs
S. No. | Guideline | Recommendation |
| ||
1 | European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) | Recommended when paracetamol or SYSADOAs and/or topical NSAIDs are not adequately effective |
| ||
2 | European League Against Rheumatism (EULAR) | Consider in patients unresponsive to paracetamol |
| ||
3 | American College of Rheumatology (ACR) | Conditionally recommended for initial therapy; strongly recommended in knee OA patients unresponsive to paracetamol |
| ||
4 | Osteoarthritis Research Society International (OARSI) | Appropriate for individuals without relevant comorbidities; uncertain for those with moderate comorbidity risk |
| ||
5 | National Institute for Health and Care Excellence (NICE) | Use when paracetamol and/or topical NSAIDs are ineffective, or in addition to paracetamol or topical NSAIDs when insufficient pain relief is achieved |
|
NSAIDs, nonsteroidal anti-inflammatory drugs; OA, osteoarthritis; SYSADOAs, symptomatic slow-acting drugs for osteoarthritis
Acetaminophen (paracetamol)
Insufficient evidence supports the use of acetaminophen in chronic LBP. Acetaminophen was found to be less effective than NSAIDs in relieving chronic LBP and knee and hip pain in osteoarthritis patients,100 while the combination of ibuprofen/acetaminophen (400 mg/1000 mg) was significantly superior to regular paracetamol 1000 mg alone (p = 0.0002) for treatment of knee pain at 13 weeks but had increased risk of GI bleeding.101
Opioids
Opioids have limited efficacy in the management of chronic pain. Moreover, they are associated with drug dependency. Evidence suggests that opioids are effective in treating chronic pain for up to 3 months.102 Importantly, long-term use of opioids over a 12-month period did not improve pain-related function and was associated with significantly more AEs than the use of nonopioids (overall, p = 0.03) in patients with chronic back pain or hip or osteoarthritis pain. The mean difference in adverse medication-related symptoms between opioids and nonopioids at 12 months was 0.9 [95% CI, 0.3–1.5]).103 Therefore, the use of opioids for non-cancer pain should be practiced with caution and with the recommendation/under the supervision of a specialized physician.
Neuropathic pain
Pain caused by a lesion or disease of the somatosensory nervous system is called neuropathic pain, which is further categorized as either peripheral or central neuropathic pain.104
Many guidelines have defined the management of neuropathic pain, which recommend tricyclic antidepressants (TCAs) (amitriptyline), serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, and calcium channel alpha-2-delta ligands (gabapentin and pregabalin) as the first-line treatment.105-107 Figures 2–4 illustrate the algorithm for the management of various types of neuropathic pain, which was adapted from National Health Service neuropathic pain management guidelines.108
Figure 2.
Neuropathic pain algorithm. CBC, complete blood count; HbA1c, glycated hemoglobin; HIV, human immunodeficiency virus; SNRI, serotonin–norepinephrine reuptake inhibitor; SSNRI, selective SNRI; TCA, tricyclic antidepressant.
Figure 4.
Algorithm for post-herpetic neuralgia. TCA, tricyclic antidepressant.
Evaluation of pain
Profile of Mood States, Hospital Anxiety and Depression Scale, and depression, Anxiety, and Stress Scales are commonly used to identify the presence of psychosocial consequences of neuropathic pain and, thus, prompt appropriate referral to allied health.92
Pharmacological treatment
TCAs
TCAs, such as amitriptyline, are recommended as the first-line treatment for neuropathic pain.15, 105-107 Evidences support the use of TCAs in the treatment of peripheral neuropathy, post-herpetic neuralgia, traumatic spinal cord injury (SCI)-induced neuropathic pain, chronic neuropathic pain, post-herpetic neuralgia, and painful diabetic neuropathy.53, 109-116 Amitriptyline and nortriptyline are found to have comparable efficacy in the treatment of peripheral neuropathic pain.117 Compared with selective serotonin reuptake inhibitors, such as fluoxetine, TCAs have shown better pain relief (p = 0.036) in antidepressant-naïve post-herpetic neuralgia patients.118 The more common AEs of these agents are nausea, dizziness, somnolence, dry mouth, diarrhea, constipation, and hyperhidrosis.119
SNRIs
SNRIs are also recommended as first-line therapy for neuropathic pain.15, 105-107 Duloxetine and venlafaxine had been demonstrated to reduce pain intensity significantly (p ≤ 0.05) in neuropathic pain patients.110, 120-124 The most common AEs reported with SNRIs are nausea, dizziness, somnolence, dry mouth, diarrhea, and constipation.125, 126
Anticonvulsants
Anticonvulsants that are commonly used for neuropathic pain are gabapentin and pregabalin.15, 105-107 Various clinical trials have investigated their effectiveness in painful diabetic neuropathy and post-herpetic neuralgia.110, 123, 127, 128 Pregabalin has shown significant pain relief (VAS score, difference from placebo 2.18; p = 0.01; adjusted difference from the placebo, 17.6; p < 0.001) in chronic central neuropathic pain following SCI.129, 130 However, it has not shown promising results in patients with neuropathic pain due to chronic lumbosacral radiculopathy and in those with central poststroke pain.131, 132
Opioids
Opioid analgesics are recommended as second-, third-, and fourth-line therapy for neuropathic pain.15, 105-107 Opioids have demonstrated their effectiveness in patients with various neuropathic pains.123, 133-138 However, a meta-analysis had reported that morphine provided moderate benefit in adults with chronic neuropathic pain.139 Long-term use of opioids is associated with a high risk of AEs and misuse.110, 140 Hence, various guidelines have raised concerns on long-term use of opioids. 15, 105-107 Weak opioids, such as tramadol, can be considered for neuropathic pain. A meta-analysis and a prospective study have shown good pain reduction with tramadol in neuropathy patients (number needed to treat for 50% pain relief vs. placebo: 4.73 [95% CI 3.6–6.7]).123, 141 However, a systematic review reported low-quality evidence for the use of tramadol in neuropathic pain.142
For further management, it is advisable to refer to a pain specialist for interventional modalities for pain management.
Discussion
Pain is a huge global health problem and one of the most common reasons for hospital visits worldwide.143 Pain management is an evolving area of expertise in Qatar, and there is an undertreatment of pain in the country because of the stigma associated with pain medications. Hence, a multidisciplinary and evidence-based approach is needed for effective pain management. Although guidance on the pharmacological treatment of peripheral neuropathic pain and acute pain is available in the Middle East,13, 15 no specific guidelines for pain management have been recommended in Qatar; currently, physicians are following American, European, Canadian, or Australian guidelines. Hence, the expert panel, after multiple meetings and discussion, derived the treatment protocol based on evidence, current international treatment guidelines, and best practice recommendations for management of acute, chronic, and neuropathic pain in Qatar.
The most appropriate treatment choice for a patient with acute pain is acetaminophen owing to its additive effect. The second-line choice is NSAIDs for acute pain of moderate intensity and referral to a pain specialist for the pain of severe intensity. For management of chronic pain, both nonpharmacologic and nonopioid pharmacologic therapies should be considered. Clinicians should refer the patients to a pain specialist if the patient needs opioid therapy. The pain specialist clinician should discuss with the patients the known risks and realistic benefits of such treatment within 1–4 weeks of starting opioid therapy.144 For neuropathic pain, antiepileptic drugs, SNRIs, and TCAs are typically recommended as the first-line treatment. Topical lidocaine and topical capsaicin are considered second-line options, while NSAIDs are not recommended for neuropathic pain.105, 107, 123 Neuropathic pain should be managed by a senior primary care physician in consultation with a pain specialist.
Experts recommended applying a precise evidence-based clinical algorithm; as a result, patients’ pain management will improve in terms of avoiding unnecessary medications, especially opioids, decreasing time to analgesia, and achieving ideal pain control in a timely manner to patient satisfaction. A standardized treatment strategy for various types of pain could help in optimizing pain management, which is currently an unmet need in Qatar.
Conclusion
An expert panel of physicians from different disciplines from Qatar, after reviewing the literature and international guidelines and discussing among the panelists, made recommendations for the management of acute, chronic, and neuropathic pain suitable for local practice and based on treatment availability in Qatar. The panel strongly recommended to avoid the use of opioids when possible and to refer the patient to a pain specialist clinician for interventional modalities of pain management as required. The panel opines that these recommendations be re-examined regularly and updated based on future developments.
Competing Interests
MA has participated in an advisory board for Eli Lilly and Pfizer and has received speaker fees from Novartis. UAS is an employee of Pfizer Upjohn and holds stock in Pfizer. OZ is an employee of Pfizer Upjohn. UAS also holds stock in Pfizer. AE and AFN have no competing interests to declare.
Funding Sources
The development of this manuscript and associated article processing charges were funded by Upjohn, a division of Pfizer. The views and opinions expressed in this article are those of the authors. They do not represent or reflect in any way the official policy or position of their current or previous employers.
Authors’ Contributions
AE, AFN, and MA contributed to the concept of this paper, identified studies to be included in this review, provided intellectual inputs for interpretation of data, and reviewed all drafts critically. OZ and UAS contributed to the concept of this paper, provided intellectual inputs for interpretation of data, and reviewed all drafts critically. All authors have read and approved the final manuscript.
Acknowledgments
The authors are grateful to all members of the Qatar Pain Expert forum working group for their valuable contributions in the development of this manuscript: Dr. Kassim Al-Anee, Dr. Osama Al Alamy, Dr. Mohammed Walid Chaarani, Dr. Nebal Shaath, Dr. Ahmed Fayed El Geziry, Dr. Ahmed Metwally Khattab, Dr. Syed Muhammad Asad, Dr. Abdul Moeen Baco, Dr. Omar AlNori, and Dr. Mohamed Sayed Abdelmoneim Sayed. The authors would like to thank Tanaya Bharatan, Lead, Medical Center of Excellence, Pfizer Upjohn, and Kaveri Sidhu, Senior Scientific Communications Specialist, Pfizer Upjohn, for providing editorial support at the meetings convened in Doha, Qatar, and for critically reviewing the manuscript.
The authors would also like to thank (Sandeep Subramaniam, Venkateswara Prasad Gali, Medical Writers) APCER Life Sciences for providing medical writing support funded by Upjohn–a division of Pfizer.
Figure 3.
Algorithm for trigeminal neuralgia. MRI, magnetic resonance imaging; TCA, tricyclic antidepressant.
References
- 1. Tompkins DA, Hobelmann JG, Compton P. Providing chronic pain management in the “Fifth Vital Sign” Era: Historical and treatment perspectives on a modern-day medical dilemma. Drug Alcohol Depend. 2017;173 Suppl 1(Suppl 1):S11–S21. [DOI] [PMC free article] [PubMed]
- 2. Raja SN, Carr DB, Cohen M, Finnerup NB, Flor H, Gibson S, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–82. [DOI] [PMC free article] [PubMed]
- 3. Orr PM, Shank BC, Black AC. The role of pain classification systems in pain management. Crit Care Nurs Clin North Am. 2017;29(4):407–18. [DOI] [PubMed]
- 4. Keating L, Smith S. Acute pain in the emergency department: The challenges. Rev Pain. 2011;5(3):13–7. [DOI] [PMC free article] [PubMed]
- 5. Wu A, March L, Zheng X, Huang J, Wang X, Zhao J, et al. Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017. Ann Transl Med. 2020;8(6):299. [DOI] [PMC free article] [PubMed]
- 6. Bener A, Dafeeah EE, Alnaqbi K, Falah O, Aljuhaisi T, Sadeeq A, et al. An epidemiologic analysis of low back pain in primary care: a hot humid country and global comparison. J Prim Care Community Health. 2013;4(3):2207. [DOI] [PubMed]
- 7. Abolfotouh SM, Mahmoud K, Faraj K, Moammer G, ElSayed A, Abolfotouh MA. Prevalence, consequences and predictors of low back pain among nurses in a tertiary care setting. Int Orthop. 2015;39(12):2439–49. [DOI] [PubMed]
- 8. White LD, Hodge A, Vlok R, Hurtado G, Eastern K, Melhuish TM. Efficacy and adverse effects of buprenorphine in acute pain management: systematic review and meta-analysis of randomised controlled trials. Br J Anaesth. 2018;120(4):668–78. [DOI] [PubMed]
- 9. Albrecht E, Taffe P, Yersin B, Schoettker P, Decosterd I, Hugli O. Undertreatment of acute pain (oligoanalgesia) and medical practice variation in prehospital analgesia of adult trauma patients: a 10 yr retrospective study. Br J Anaesth. 2013;110(1):96–106. [DOI] [PubMed]
- 10. Motov SM, Khan AN. Problems and barriers of pain management in the emergency department: Are we ever going to get better? J Pain Res. 2008;2:5–11. [PMC free article] [PubMed]
- 11. Motov SM, Nelson LS. Advanced concepts and controversies in emergency department pain management. Anesthesiol Clin. 2016;34(2):271–85. [DOI] [PubMed]
- 12. Foster NE, Mullis R, Hill JC, Lewis M, Whitehurst DG, Doyle C, et al. Effect of stratified care for low back pain in family practice (IMPaCT Back): a prospective population-based sequential comparison. Ann Fam Med. 2014;12(2):102–11. [DOI] [PMC free article] [PubMed]
- 13. Ayad AE, Ghaly N, Ragab R, Majeed S, Nassar H, Al Jalabi A, et al. Expert panel consensus recommendations for the pharmacological treatment of acute pain in the Middle East region. J Int Med Res. 2011;39(4):1123–41. [DOI] [PubMed]
- 14. Bouri F, El Ansari W, Mahmoud S, Elhessy A, Al-Ansari A, Al-Dosari MAA. Orthopedic professionals’ recognition and knowledge of pain and perceived barriers to optimal pain management at five hospitals. Healthcare (Basel). 2018;6(3) [DOI] [PMC free article] [PubMed]
- 15. Bohlega S, Alsaadi T, Amir A, Hosny H, Karawagh AM, Moulin D, et al. Guidelines for the pharmacological treatment of peripheral neuropathic pain: expert panel recommendations for the middle East region. J Int Med Res. 2010;38(2):295–317. [DOI] [PubMed]
- 16. Acute Pain Management in Emergency and Acute Care Settings [Internet]. Pain Management and Assessment Initiative (PAMI): A Patient Safety Project. 2016.
- 17. Breivik H, Borchgrevink PC, Allen SM, Rosseland LA, Romundstad L, Hals EK, et al. Assessment of pain. Br J Anaesth. 2008;101(1):17–24. [DOI] [PubMed]
- 18. Tsze DS, Pan SS, DePeter KC, Wagh AM, Gordon SL, Dayan PS. Intranasal hydromorphone for treatment of acute pain in children: A pilot study. Am J Emerg Med. 2019;37(6):1128–32. [DOI] [PubMed]
- 19. Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical activity/exercise and diabetes: A position statement of the American diabetes association. Diabetes Care. 2016;39(11):2065–79. [DOI] [PMC free article] [PubMed]
- 20. Sharma CV. Paracetamol: mechanisums and udpates.continuing education in anaesthesia critical care & cain. 2014;14(4):153–8.
- 21. Shiffman S, Battista DR, Kelly JP, Malone MK, Weinstein RB, Kaufman DW. Prevalence of exceeding maximum daily dose of paracetamol, and seasonal variations in cold-flu season. Br J Clin Pharmacol. 2018;84(6):1250–7. [DOI] [PMC free article] [PubMed]
- 22. Lyrtzis C, Natsis K, Papadopoulos C, Noussios G, Papathanasiou E. Efficacy of paracetamol versus diclofenac for Grade II ankle sprains. Foot Ankle Int. 2011;32(6):571–5. [DOI] [PubMed]
- 23. Bondarsky EE, Domingo AT, Matuza NM, Taylor MB, Thode HC, Jr., Singer AJ. Ibuprofen vs acetaminophen vs their combination in the relief of musculoskeletal pain in the ED: a randomized, controlled trial. Am J Emerg Med. 2013;31(9):1357–60. [DOI] [PubMed]
- 24. Buccelletti F, Marsiliani D, Zuccalà G, Iacomini P, Proietti L, Pola E, et al. Paracetamol-codeine compared to ketorolac for pain control in the Emergency Department. Eur Rev Med Pharmacol Sci. 2014;18(20):3139–43. [PubMed]
- 25. Ridderikhof ML, Lirk P, Goddijn H, Vandewalle E, Schinkel E, Van Dieren S, et al. Acetaminophen or nonsteroidal anti-inflammatory drugs in acute musculoskeletal trauma: A multicenter, double-blind, randomized, clinical trial. Ann Emerg Med. 2018;71(3):357–68 e8. [DOI] [PubMed]
- 26. Oyler DR, Parli SE, Bernard AC, Chang PK, Procter LD, Harned ME. Nonopioid management of acute pain associated with trauma: Focus on pharmacologic options. J Trauma Acute Care Surg. 2015;79(3):475–83. [DOI] [PubMed]
- 27. Jahr JS, Filocamo P, Singh S. Intravenous acetaminophen: a review of pharmacoeconomic science for perioperative use. Am J Ther. 2013;20(2):189–99. [DOI] [PubMed]
- 28. Apfel CC, Turan A, Souza K, Pergolizzi J, Hornuss C. Intravenous acetaminophen reduces postoperative nausea and vomiting: a systematic review and meta-analysis. Pain. 2013;154(5):677–89. [DOI] [PubMed]
- 29. Blanco JS, Perlman SL, Cha HS, Delpizzo K. Multimodal pain management after spinal surgery for adolescent idiopathic scoliosis. Orthopedics. 2013;36(2 Suppl):33–5. [DOI] [PubMed]
- 30. Tsang KS, Page J, Mackenney P. Can intravenous paracetamol reduce opioid use in preoperative hip fracture patients? Orthopedics. 2013;36(2 Suppl):20–4. [DOI] [PubMed]
- 31. Lachiewicz PF. The role of intravenous acetaminophen in multimodal pain protocols for perioperative orthopedic patients. Orthopedics. 2013;36(2 Suppl):15–9. [DOI] [PubMed]
- 32. Ceelie I, de Wildt SN, van Dijk M, van den Berg MM, van den Bosch GE, Duivenvoorden HJ, et al. Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: a randomized controlled trial. JAMA. 2013;309(2):149–54. [DOI] [PubMed]
- 33. Bektas F, Eken C, Karadeniz O, Goksu E, Cubuk M, Cete Y. Intravenous paracetamol or morphine for the treatment of renal colic: a randomized, placebo-controlled trial. Ann Emerg Med. 2009;54(4):568–74. [DOI] [PubMed]
- 34. Serinken M, Eken C, Turkcuer I, Elicabuk H, Uyanik E, Schultz CH. Intravenous paracetamol versus morphine for renal colic in the emergency department: a randomised double-blind controlled trial. Emerg Med J. 2012;29(11):902–5. [DOI] [PubMed]
- 35. Azizkhani R, Pourafzali SM, Baloochestani E, Masoumi B. Comparing the analgesic effect of intravenous acetaminophen and morphine on patients with renal colic pain referring to the emergency department: A randomized controlled trial. J Res Med Sci. 2013;18(9):772–6. [PMC free article] [PubMed]
- 36. Masoumi K, Forouzan A, Asgari Darian A, Feli M, Barzegari H, Khavanin A. Comparison of clinical efficacy of intravenous acetaminophen with intravenous morphine in acute renal colic: a randomized, double-blind, controlled trial. Emerg Med Int. 2014;2014:571326. [DOI] [PMC free article] [PubMed]
- 37. Hartling L, Ali S, Dryden DM, Chordiya P, Johnson DW, Plint AC, et al. How safe are common analgesics for the treatment of acute pain for children? A systematic review. Pain Res Manag. 2016;2016:5346819. [DOI] [PMC free article] [PubMed]
- 38. Moore N, Pollack C, Butkerait P. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag. 2015;11:1061–75. [DOI] [PMC free article] [PubMed]
- 39. Schink T, Kollhorst B, Varas Lorenzo C, Arfè A, Herings R, Lucchi S, et al. Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project. PLoS One. 2018;13(9):e0203362. [DOI] [PMC free article] [PubMed]
- 40. Klein A, Eliakim R. Non steroidal anti-inflammatory drugs and inflammatory bowel disease. Pharmaceuticals (Basel). 2010;3(4):1084–92. [DOI] [PMC free article] [PubMed]
- 41. Gimbel JS, Brugger A, Zhao W, Verburg KM, Geis GS. Efficacy and tolerability of celecoxib versus hydrocodone/acetaminophen in the treatment of pain after ambulatory orthopedic surgery in adults. Clin Ther. 2001;23(2):228–41. [DOI] [PubMed]
- 42. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: A randomized clinical trial. JAMA. 2015;314(15):1572–80. [DOI] [PubMed]
- 43. Pathan SA, Mitra B, Cameron PA. A systematic review and meta-analysis comparing the efficacy of nonsteroidal anti-inflammatory drugs, opioids, and paracetamol in the Treatment of Acute Renal Colic. Eur Urol. 2018;73(4):583–95. [DOI] [PubMed]
- 44. Pathan SA, Mitra B, Straney LD, Afzal MS, Anjum S, Shukla D, et al. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial. Lancet. 2016;387(10032):1999–2007. [DOI] [PubMed]
- 45. Qureshi I, Pathan SA, Qureshi RS, Thomas SH. Intramuscular versus oral diclofenac for acute pain in adults with acute musculoskeletal injuries presenting to the ED setting: a prospective, double-blind, double-dummy, randomised controlled trial. Emerg Med J. 2019;36(7):401–6. [DOI] [PubMed]
- 46. Ortiz MI, Monroy-Maya R Fau - Soto-Ríos M, Soto-Ríos M Fau - Carrillo-Alarcón LC, et al. Effectiveness of diclofenac, ketorolac and etoricoxib in the treatment of acute pain from ankle fracture. Proc West Pharmacol Soc. 2010;53:46–8. [PubMed]
- 47. Wright JM, Price SD, Watson WA. NSAID use and efficacy in the emergency department: single doses of oral ibuprofen versus intramuscular ketorolac. Ann Pharmacother. 1994;28(3):309-12. [DOI] [PubMed]
- 48. Turturro MA, Paris PM, Seaberg DC. Intramuscular ketorolac versus oral ibuprofen in acute musculoskeletal pain. Ann Emerg Med. 1995;26(2):117–20. [DOI] [PubMed]
- 49. Plapler PG, Scheinberg MA, Ecclissato Cda C, Bocchi de Oliveira MF, Amazonas RB. Double-blind, randomized, double-dummy clinical trial comparing the efficacy of ketorolac trometamol and naproxen for acute low back pain. Drug Des Devel Ther. 2016;10:1987–93. [DOI] [PMC free article] [PubMed]
- 50. Motov S, Yasavolian M, Likourezos A, Pushkar I, Hossain R, Drapkin J, et al. Comparison of intravenous ketorolac at three single-dose regimens for treating acute pain in the emergency department: A randomized controlled trial. Ann Emerg Med. 2017;70(2):177–84. [DOI] [PubMed]
- 51. Baharuddin KA, Rahman NH, Wahab SF, Halim NA, Ahmad R. Intravenous parecoxib sodium as an analgesic alternative to morphine in acute trauma pain in the emergency department. Int J Emerg Med. 2014;7(1):2. [DOI] [PMC free article] [PubMed]
- 52. Lloyd R, Derry S, Moore RA, McQuay HJ. Intravenous or intramuscular parecoxib for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009;2009(2):CD004771. [DOI] [PMC free article] [PubMed]
- 53. Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;1(1):CD011209. [DOI] [PMC free article] [PubMed]
- 54. Baraf HS, Gloth FM, Barthel HR, Gold MS, Altman RD. Safety and efficacy of topical diclofenac sodium gel for knee osteoarthritis in elderly and younger patients: pooled data from three randomized, double-blind, parallel-group, placebo-controlled, multicentre trials. Drugs Aging. 2011;28(1):27–40. [DOI] [PubMed]
- 55. Bariguian Revel F, Fayet M, Hagen M. Topical diclofenac, an efficacious treatment for osteoarthritis: A narrative review. Rheumatol Ther. 2020;7(2):217–36. [DOI] [PMC free article] [PubMed]
- 56. Oguzturk H, Ozgur D, Turtay MG, Kayaalp C, Yilmaz S, Dogan M, et al. Tramadol or paracetamol do not effect the diagnostic accuracy of acute abdominal pain with significant pain relief - a prospective, randomized, placebo controlled double blind study. Eur Rev Med Pharmacol Sci. 2012;16(14):1983–8. [PubMed]
- 57. Mortelmans LJ, Desruelles D, Baert JA, Hente KR, Tailly GG. Use of tramadol drip in controlling renal colic pain. J Endourol. 2006;20(12):1010–5. [DOI] [PubMed]
- 58. Engindeniz Z, Demircan C, Karli N, Armagan E, Bulut M, Aydin T, et al. Intramuscular tramadol vs. diclofenac sodium for the treatment of acute migraine attacks in emergency department: a prospective, randomised, double-blind study. J Headache Pain. 2005;6(3):143–8. [DOI] [PMC free article] [PubMed]
- 59. Park YB, Ha CW, Cho SD, Lee MC, Lee JH, Seo SS, et al. A randomized study to compare the efficacy and safety of extended-release and immediate-release tramadol HCl/acetaminophen in patients with acute pain following total knee replacement. Curr Med Res Opin. 2015;31(1):75–84. [DOI] [PubMed]
- 60. Bugada D, Lavand'homme P, Ambrosoli AL, Klersy C, Braschi A, Fanelli G, et al. Effect of postoperative analgesia on acute and persistent postherniotomy pain: a randomized study. J Clin Anesth. 2015;27(8):658–64. [DOI] [PubMed]
- 61. Moore RA, McQuay HJ, Tomaszewski J, Raba G, Tutunaru D, Lietuviete N, et al. Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe acute pain after abdominal hysterectomy. BMC Anesthesiol. 2016;16:9. [DOI] [PMC free article] [PubMed]
- 62. Bouida W, Beltaief K, Msolli MA, Ben Marzouk M, Boubaker H, Grissa MH, et al. Effect on Morphine Requirement of Early Administration of Oral Acetaminophen vs. Acetaminophen/Tramadol Combination in Acute Pain. Pain Pract. 2019;19(3):275–82. [DOI] [PubMed]
- 63. Zarghami M, Masoum B, Shiran MR, Lanier RK, Lofwall MR, Mintzer MZ, et al. Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial Physical dependence potential of daily tramadol dosing in humans. J Addict Dis. 2012;31(2):112–7. [DOI] [PubMed]
- 64. Lofwall MR, Walsh SL, Bigelow GE, Strain EC, Adams EH, Breiner S, et al. Modest opioid withdrawal suppression efficacy of oral tramadol in humans. Psychopharmacol (Berl). 2007;194(3):381–93. [DOI] [PubMed]
- 65. Dunn KE, Tompkins DA, Bigelow GE, Strain EC. Efficacy of Tramadol Extended-Release for Opioid Withdrawal: A Randomized Clinical Trial. JAMA Psychiatry. 2017;74(9):885–93. [DOI] [PMC free article] [PubMed]
- 66. Das M, Jain R, Dhawan A, Kaur A, Lofwall MR, Babalonis S, et al. Assessment of abuse liability of Tramadol among experienced drug users: Double-blind crossover randomized controlled trial Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial. J Opioid Manag. 2016;12(6):421–30. [DOI] [PubMed]
- 67. Lofwall MR, Babalonis S, Nuzzo PA, Siegel A, Campbell C, Walsh SL. Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial. Drug Alcohol Depend. 2013;133(1):188–97. [DOI] [PMC free article] [PubMed]
- 68. Lanier RK, Lofwall MR, Mintzer MZ, Bigelow GE, Strain EC. Physical dependence potential of daily tramadol dosing in humans. Psychopharmacology (Berl). 2010;211(4):457–66. [DOI] [PMC free article] [PubMed]
- 69. Adams EH, Breiner S, Cicero TJ, Geller A, Inciardi JA, Schnoll SH, et al. A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J Pain Symptom Manage. 2006;31(5):465–76. [DOI] [PubMed]
- 70. Knisely JS, Campbell ED, Dawson KS, Schnoll SH, Camí J, Lamas X, et al. Tramadol post-marketing surveillance in health care professionals. Drug Alcohol Depend. 2002;68(1):15–22. [DOI] [PubMed]
- 71. Camí J, Lamas X, Farré M, Preston KL, Jasinski DR, Testa M, et al. Acute effects of tramadol in methadone-maintained volunteers. Drugs. 1994;47 Suppl 1(1):39–43. [DOI] [PubMed]
- 72. Preston KL, Jasinski DR, Testa M, Richter W, Barth H, Flohé L, et al. Abuse potential and pharmacological comparison of tramadol and morphine. Drug Alcohol Depend. 1991;27(1):7–17. [DOI] [PubMed]
- 73. Richter W, Barth H, Flohé L, Giertz H. Clinical investigation on the development of dependence during oral therapy with tramadol. Arzneimittelforschung. 1985;35(11):1742–4. [PubMed]
- 74. Chidambaran V, Sadhasivam S, Mahmoud M. Codeine and opioid metabolism: implications and alternatives for pediatric pain management. Curr Opin Anaesthesiol. 2017;30(3):349–56. [DOI] [PMC free article] [PubMed]
- 75. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use - United States, 2006–2015. MMWR Morb Mortal Wkly Rep. 2017;66(10):265–9. [DOI] [PMC free article] [PubMed]
- 76. Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372(3):241–8. [DOI] [PubMed]
- 77. Nasser SC, Nassif JG, Saad AH. Physicians’ attitudes to clinical pain management and education: Survey from a middle Eastern country. Pain Res Manag. 2016;2016:1358593. [DOI] [PMC free article] [PubMed]
- 78. Motov S, Mann S, Drapkin J, Butt M, Likourezos A, Yetter E, et al. Intravenous subdissociative-dose ketamine versus morphine for acute geriatric pain in the Emergency Department: A randomized controlled trial. Am J Emerg Med. 2019;37(2):220–7. [DOI] [PubMed]
- 79. Karlow N, Schlaepfer CH, Stoll CRT, Doering M, Carpenter CR, Colditz GA, et al. A systematic review and meta-analysis of Ketamine as an alternative to opioids for acute pain in the emergency department. Acad Emerg Med. 2018;25(10):1086–97. [DOI] [PubMed]
- 80. Dinges HC, Otto S, Stay DK, Bäumlein S, Waldmann S, Kranke P, et al. Side effect rates of opioids in equianalgesic doses via intravenous patient-controlled analgesia: A systematic review and network meta-analysis. Anesth Analg. 2019;129(4):1153–62. [DOI] [PubMed]
- 81. Tan HP, Conroy T. The effectiveness of intravenous Oxycodone in the treatment of acute postoperative pain: A systematic review. J Perianesth Nurs. 2018;33(6):865–79. [DOI] [PubMed]
- 82. Miner JR, Melson TI, Leiman D, Minkowitz HS, Chiang YK, DiDonato KP, et al. Pooled Phase III safety analysis of sufentanil sublingual tablets for short-term treatment of moderate-to-severe acute pain. Pain Manag. 2019;9(3):259–71. [DOI] [PubMed]
- 83. Brinck EC, Tiippana E, Heesen M, Bell RF, Straube S, Moore RA, et al. Perioperative intravenous ketamine for acute postoperative pain in adults. Cochrane Database Syst Rev. 2018;12(12):CD012033. [DOI] [PMC free article] [PubMed]
- 84. Sin B, Jeffrey I, Halpern Z, Adebayo A, Wing T, Lee AS, et al. Intranasal sufentanil versus intravenous morphine for acute pain in the emergency department: A randomized pilot trial. J Emerg Med. 2019;56(3):301–7. [DOI] [PubMed]
- 85. Chinn E, Friedman BW, Naeem F, Irizarry E, Afrifa F, Zias E, et al. Randomized Trial of Intravenous Lidocaine Versus Hydromorphone for Acute Abdominal Pain in the Emergency Department. Ann Emerg Med. 2019;74(2):233–40. [DOI] [PMC free article] [PubMed]
- 86. Singla NK, Skobieranda F, Soergel DG, Salamea M, Burt DA, Demitrack MA, et al. APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the μ-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty. Pain Pract. 2019;19(7):715–31. [DOI] [PMC free article] [PubMed]
- 87. Blancher M, Maignan M, Clapé C, Quesada JL, Collomb-Muret R, Albasini F, et al. Intranasal sufentanil versus intravenous morphine for acute severe trauma pain: A double-blind randomized non-inferiority study. PLoS Med. 2019;16(7):e1002849. [DOI] [PMC free article] [PubMed]
- 88. Raffaeli W, Arnaudo E. Pain as a disease: an overview. J Pain Res. 2017;10:2003–8. [DOI] [PMC free article] [PubMed]
- 89. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–7. [DOI] [PMC free article] [PubMed]
- 90. American Pain Society. Pain: Current Understanding of Assessment, Management, and Treatments. [Available from: https://www.npcnow.org/system/files/research/download/Pain-Current-Understanding-of-Assessment-Management-and-Treatments.pdf.
- 91. Human Rights Watch. Global State of Pain Treatment. 2011.
- 92. Bates D, Schultheis BC, Hanes MC, Jolly SM, Chakravarthy KV, Deer TR, et al. A comprehensive algorithm for management of neuropathic pain. Pain Med. 2019;20(Suppl 1):S2–S12. [DOI] [PMC free article] [PubMed]
- 93. CDC. https://www.cdc.gov/drugoverdose/training/nonopioid/508c/index.html.
- 94. Pelletier JP, Martel-Pelletier J, Rannou F, Cooper C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: Evidence from real-life setting trials and surveys. Semin Arthritis Rheum. 2016;45(4 Suppl):S22–7. [DOI] [PubMed]
- 95. American Diabetes Association. 5. Lifestyle Management: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S46–S60. [DOI] [PubMed]
- 96. Chou R, Deyo R, Friedly J, Skelly A, Weimer M, Fu R, et al. Systemic pharmacologic therapies for low back pain: A systematic review for an American college of physicians clinical practice guideline. Ann Intern Med. 2017;166(7):480–92. [DOI] [PubMed]
- 97. Enthoven WT, Roelofs PD, Deyo RA, van Tulder MW, Koes BW. Non-steroidal anti-inflammatory drugs for chronic low back pain. Cochrane Database Syst Rev. 2016;2(2):CD012087. [DOI] [PMC free article] [PubMed]
- 98. Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev. 2008(1):CD000396. [DOI] [PMC free article] [PubMed]
- 99. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769–79. [DOI] [PMC free article] [PubMed]
- 100. Davies RA, Maher CG, Hancock MJ. A systematic review of paracetamol for non-specific low back pain. Eur Spine J. 2008;17(11):1423–30. [DOI] [PMC free article] [PubMed]
- 101. Doherty M, Hawkey C, Goulder M, Gibb I, Hill N, Aspley S, et al. A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain. Ann Rheum Dis. 2011;70(9):1534–41. [DOI] [PubMed]
- 102. Meske DS, Lawal OD, Elder H, Langberg V, Paillard F, Katz N. Efficacy of opioids versus placebo in chronic pain: a systematic review and meta-analysis of enriched enrollment randomized withdrawal trials. J Pain Res. 2018;11:923–34. [DOI] [PMC free article] [PubMed]
- 103. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, et al. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: The SPACE randomized clinical trial. JAMA. 2018;319(9):872–82. [DOI] [PMC free article] [PubMed]
- 104. cited 15 Jul 2020]. Available from: = https://www.iasp-pain.org/Education/Content.aspx?ItemNumber = 1698.
- 105. Attal N, Cruccu G, Baron R, Haanpää M, Hansson P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113–e88. [DOI] [PubMed]
- 106. Neuropathic Pain: The Pharmacological Management of Neuropathic Pain in Adults in Non-specialist Settings. London: © 2013, National Institute for Health and Care Excellence; 2013 Nov. [PubMed]
- 107. Mu A WE, Moulin DE, Clarke H. Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement. Can Fam Physician. 2017;63(11):844–52. [PMC free article] [PubMed]
- 108. Julia Oxley KET, Tim Daniel, Mike McHugh, Nick Willmot. Leicestershire Medicines Strategy Group. Guideline for treating patients with neuropathic pain. May 2009.
- 109. Agarwal N, Joshi M. Effectiveness of amitriptyline and lamotrigine in traumatic spinal cord injury-induced neuropathic pain: a randomized longitudinal comparative study. Spinal Cord. 2017;55(2):126–30. [DOI] [PubMed]
- 110. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150(3):573–81. [DOI] [PubMed]
- 111. Gilron I, Tu D, Holden RR, Jackson AC, DuMerton-Shore D. Combination of morphine with nortriptyline for neuropathic pain. Pain. 2015;156(8):1440–8. [DOI] [PubMed]
- 112. Hempenstall K, Nurmikko TJ, Johnson RW, A'Hern RP, Rice AS. Analgesic therapy in post-herpetic neuralgia: a quantitative systematic review. PLoS Med. 2005;2(7):e164. [DOI] [PMC free article] [PubMed]
- 113. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015;2015(7):CD008242. [DOI] [PMC free article] [PubMed]
- 114. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007(4):CD005454. [DOI] [PMC free article] [PubMed]
- 115. Calandre EP, Rico-Villademoros F, Galán J, Molina-Barea R, Vilchez JS, Rodriguez-Lopez CM, et al. Quetiapine extended-release (Seroquel-XR) versus amitriptyline monotherapy for treating patients with fibromyalgia: a 16-week, randomized, flexible-dose, open-label trial. Psychopharmacology (Berl). 2014;231(12):2525–31. [DOI] [PubMed]
- 116. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2012;12:CD008242. [DOI] [PubMed]
- 117. Liu WQ, Kanungo A, Toth C. Equivalency of tricyclic antidepressants in open-label neuropathic pain study. Acta Neurol Scand. 2014;129(2):132–41. [DOI] [PubMed]
- 118. Rowbotham MC, Reisner LA, Davies PS, Fields HL. Treatment response in antidepressant-naïve post-herpetic neuralgia patients: double-blind, randomized trial. J Pain. 2005;6(11):741–6. [DOI] [PubMed]
- 119. Rheker J, Rief W, Doering BK, Winkler A. Assessment of adverse events in clinical drug trials: Identifying amitriptyline's placebo- and baseline-controlled side effects. Exp Clin Psychopharmacol. 2018;26(3):320–6. [DOI] [PubMed]
- 120. Sindrup SH, Bach FW, Madsen C, Gram LF, Jensen TS. Venlafaxine versus imipramine in painful polyneuropathy: a randomized, controlled trial. Neurology. 2003;60(8):1284–9. [DOI] [PubMed]
- 121. Rowbotham MC, Goli V, Kunz NR, Lei D. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study. Pain. 2004;110(3):697–706. [DOI] [PubMed]
- 122. Vranken JH, Hollmann MW, van der Vegt MH, Kruis MR, Heesen M, Vos K, et al. Duloxetine in patients with central neuropathic pain caused by spinal cord injury or stroke: a randomized, double-blind, placebo-controlled trial. Pain. 2011;152(2):267–73. [DOI] [PubMed]
- 123. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–73. [DOI] [PMC free article] [PubMed]
- 124. Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014;2014(5):CD010769. [DOI] [PMC free article] [PubMed]
- 125. Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol. 2008;8:29. [DOI] [PMC free article] [PubMed]
- 126. Gahimer J, Wernicke J, Yalcin I, Ossanna MJ, Wulster-Radcliffe M, Viktrup L. A retrospective pooled analysis of duloxetine safety in 23,983 subjects. Curr Med Res Opin. 2007;23(1):175–84. [DOI] [PubMed]
- 127. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil. 2007;88(12):1547–60. [DOI] [PubMed]
- 128. Gordh TE, Stubhaug A, Jensen TS, Arnèr S, Biber B, Boivie J, et al. Gabapentin in traumatic nerve injury pain: a randomized, double-blind, placebo-controlled, cross-over, multi-center study. Pain. 2008;138(2):255–66. [DOI] [PubMed]
- 129. Vranken JH, Dijkgraaf MG, Kruis MR, van der Vegt MH, Hollmann MW, Heesen M. Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain. 2008;136(1–2):150–7. [DOI] [PubMed]
- 130. Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67(10):1792–800. [DOI] [PubMed]
- 131. Kim JS, Bashford G, Murphy TK, Martin A, Dror V, Cheung R. Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain. 2011;152(5):1018–23. [DOI] [PubMed]
- 132. Baron R, Freynhagen R, Tölle TR, Cloutier C, Leon T, Murphy TK, et al. The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy. Pain. 2010;150(3):420–7. [DOI] [PubMed]
- 133. Gimbel JS, Richards P, Portenoy RK. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology. 2003;60(6):927–34. [DOI] [PubMed]
- 134. Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain and cortical reorganization. Pain. 2001;90(1–2):47–55. [DOI] [PubMed]
- 135. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA. 2005;293(24):3043–52. [DOI] [PubMed]
- 136. Raja SN, Haythornthwaite JA, Pappagallo M, Clark MR, Travison TG, Sabeen S, et al. Opioids versus antidepressants in post-herpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2002;59(7):1015–21. [DOI] [PubMed]
- 137. Watson CP, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in post-herpetic neuralgia. Neurology. 1998;50(6):1837–41. [DOI] [PubMed]
- 138. Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105(1–2):71–8. [DOI] [PubMed]
- 139. Cooper TE, Chen J, Wiffen PJ, Derry S, Carr DB, Aldington D, et al. Morphine for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017;5(5):CD011669. [DOI] [PMC free article] [PubMed]
- 140. Portenoy RK, Farrar JT, Backonja MM, Cleeland CS, Yang K, Friedman M, et al. Long-term use of controlled-release oxycodone for non-cancer pain: results of a 3-year registry study. Clin J Pain. 2007;23(4):287–99. [DOI] [PubMed]
- 141. Saxena AK, Nasare N, Jain S, Dhakate G, Ahmed RS, Bhattacharya SN, et al. A randomized, prospective study of efficacy and safety of oral tramadol in the management of post-herpetic neuralgia in patients from north India. Pain Pract. 2013;13(4):264–75. [DOI] [PubMed]
- 142. Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6(6):CD003726. [DOI] [PMC free article] [PubMed]
- 143. Almehlisi A, Tainter C. Emergency department pain management: beyond opioids. Emerg Med Pract. 2019;21(11):1–24. [PubMed]
- 144. Abu-Ashour W, Twells L, Valcour J, Randell A, Donnan J, Howse P, et al. The association between diabetes mellitus and incident infections: a systematic review and meta-analysis of observational studies. BMJ Open Diabetes Res Care. 2017;5(1):e000336. [DOI] [PMC free article] [PubMed]