Open access peer-reviewed chapter

Multimodal Pharmacological Analgesia in Pain Management

Written By

Antonella Paladini and Giustino Varrassi

Submitted: 28 May 2020 Reviewed: 17 August 2020 Published: 03 September 2020

DOI: 10.5772/intechopen.93620

From the Edited Volume

Pain Management - Practices, Novel Therapies and Bioactives

Edited by Viduranga Yashasvi Waisundara, Ines Banjari and Jelena Balkić

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The knowledge of the pathophysiology of pain has gradually evolved in recent years, allowing the development of new management strategies, more specifically addressing single pain types and patient profiles. Despite these advancements, pain management still remains an open issue, given the limitations of single agent therapies, the potential abuse/misuse of opioids and the risk of adverse events. The advent of multimodal analgesic strategies paves the way for major improvements in pain management, combining increased efficacy with better tolerability and an opioid-sparing effect. The association of analgesics with different mechanisms of action represents a successful strategy for a wide range of pain conditions, minimizing side effects and taking advantage of the additive or synergistic actions of individual agents. Last but not least, the increasing availability of oral fixed-dose combinations of analgesics will offer further advantages over extemporaneous combinations, by increasing ease of administration and patient adherence to treatment.


  • acute pain
  • chronic pain
  • analgesia
  • multimodal
  • drug combination
  • opioid
  • anti-inflammatory agents
  • nonsteroidal
  • acetaminophen

1. Introduction

Whatever its cause, pain, both acute and chronic, often emerges from multiple pathogenic pathways [1], which makes drug treatment particularly difficult [2]. In recent decades, the pharmacological arsenal against pain, in addition to traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol, has been enriched, on the one hand with molecules operating on different pain mechanisms (as anticonvulsants and antidepressants), and on the other hand with opioids [3]. However, the single-agent approach to pain remains quite challenging, since a single drug, acting on a single pain component, is generally not successful to achieve a clinically meaningful pain reduction, whereas its use at high doses may cause significant side effects [2]. On the other hand, the increasing prescription of opioids for noncancer chronic pain, besides providing limited clinical advantage compared with non-opioid alternatives [4], has opened the door to problematic opioid use and addiction problems: up to 50% of patients on long-term opioid therapy develop physical dependence or tolerance, leading to problematic opioid use in 5–10% of patients and to addiction in 1–2% [5]. As a consequence, pain management is far from being optimal and patients are exposed to the risks associated with misuse of single agents [6, 7].

Considering the complexity of pain pathogenesis, which involves multiple pathways [1], and the difficulty to reach complete symptoms control, especially for chronic pain which still affects 25–35% of adults in Europe [8], multimodal pharmacological analgesia may represent a possible solution to the still unsolved problem of pain management, thanks to a number of potential advantages: first, a decrease of the administered doses of the individual components; second, the reduction of side effects; and third, a simultaneous action on different pain components [9]. Thanks to these features, multimodal pharmacological therapy gives clinicians the opportunity to make a further step forward to a fully individualized therapy of pain in its various components and clinical manifestations [3].

In this chapter, we will present the therapeutic strategies currently available to address the specific needs in the treatment of different painful conditions and the new possibilities for pain intervention according to the multimodal approach.


2. Pain management: unmet needs and future challenges

Despite the multiple treatment options available, pain remains a mostly unresolved topic in every day clinical practice. The analgesic efficacy of single drug treatment is often not sufficient to provide an adequate pain relief, since most analgesic drugs cannot be prescribed at unlimited doses due to the ceiling effect and safety concerns. Another limitation of single-agent analgesia is that it cannot address the multiple pathways underlying pain pathogenesis. Combining drugs from different classes, with different and complementary mechanisms of action, may provide a better opportunity for effective analgesia at reduced doses of individual agents, with a potential reduction of dose-related adverse events.

Based on these considerations, clinical practice is gradually moving from a traditional one-fits-all approach to a more tailored strategy. The traditional approach to pain management refers to the three-step World Health Organization (WHO) pain ladder, which recommends the following regimen, based on the intensity of the patient’s pain [10]:

  1. Step I: a non-opioid analgesic should be used for moderate pain, with co-analgesics if necessary.

  2. Step II: if pain persists or increases, a weak opioid may be added.

  3. Step III: if pain still persists, then a change should be made to a strong opioid.

By contrast, newer guidelines aim at treating pain according to the mechanism or mechanisms involved, i.e., neuropathic, nociceptive, or a combination of both [11]. Clinicians should seek to identify the basic pain mechanisms and treat the patient, accordingly, choosing the drug with the most appropriate mechanism of action [6].

Pain is a complex construct with sophisticated transmission pathways in the nervous system, which can be altered physiologically or pharmacologically [2]. Modulation of the transmission of pain can be divided into three approaches:

  1. Modulating the upward transmission

  2. Altering perception centrally

  3. Modulating descending inhibitory pathways

Intervening in all three areas with multiple drugs is more effective than single drug treatment, and it allows to reduce the total dose of any one drug, thereby limiting unwanted effects [9].

Different drugs act at different areas:

  1. Peripherally acting drugs:

    • Local anesthetics

    • NSAIDS

  2. Drugs acting in the spinal cord:

    • Opiates

    • NSAIDS

    • N-methyl-D-aspartate (NMDA) receptor antagonists

    • Gabapentinoids

  3. Drugs acting centrally:

    • Opiates

    • Paracetamol

  4. Drugs acting on descending pathways:

    • Tramadol

    • Clonidine

    • 5HT3 antagonists

The principle of multimedia analgesia is the use of a number of drugs (analgesic or adjuvant) in combination to achieve the best pain relief in acute or chronic pain. Combining analgesics that act by different mechanisms of action allows modulating multiple transmission pathways and enables individual agents to act with potentially additive or synergistic effects [12].

Multimodal analgesia is widely acknowledged to be superior to a single drug approach, having demonstrated improved pain relief, with the fewest side effects [2]. This concept was pharmacologically studied in the 1960s by Houde et al. [13], then clinically suggested (especially in postoperative pain) in the 1980s [14], and a few years later diffused by Kehlet and Dahl [9], who first introduced the term “multimodal” or “blended” analgesia. Since then, multimodal analgesia has been deeply studied, demonstrating a broader spectrum of action, greater efficacy, better patient compliance, and an improved efficacy/safety ratio compared with monotherapy [12]. As a result, analgesic combinations are recommended by the WHO, American Pain Society (APS), and American College of Rheumatology (ACR) [15, 16, 17] and are commonly used in clinical practice. As regards the ease of use, fixed-dose combinations (FDCs) may offer additional advantages, including ease of administration, reduction of pill burden, and improved adherence [18].


3. Analgesic drug combinations

The pharmacological therapeutic approach of multimodal analgesia includes all the frontline drugs available, used alone or in combination according to the specific needs of the patient [19].

Drugs for pain control fall into four main categories [20]:

  1. weak analgesics (paracetamol and metamizole)

  2. NSAIDs (ibuprofen, diclofenac, ketoprofen, and dexketoprofen)

  3. opioids (morphine, hydromorphone, and oxycodone)

  4. adjuvant drugs (antidepressant, antiepileptic medications, corticosteroids, colchicine, neurotrophine, and biologic drugs)

The choice of the most appropriate drug combination should consider the pathogenic mechanisms of pain and satisfy the following criteria:

  • The drugs to be combined should have different mechanisms of action and preferably act at different sites;

  • The drugs to be combined should not interfere with the preexisting comorbidities of the patient; and

  • FDCs should be preferred, if available, aiming at improving patient adherence to therapy.

Different drugs with different mechanism(s) of action may be combined for enhanced efficacy [20]. Analgesics relieve pain through a variety of mechanisms of action along multiple sites of the nociceptive pathway (Table 1) [3].

Drug Mechanism of action
Paracetamol Inhibits prostaglandin synthesis in the central nervous system.
NSAIDs Inhibit prostaglandin production by blocking cyclooxygenase both peripherally and centrally.
Opioids Have multiple sites of action:
  • In the brain, they activate descending pain inhibitors.

  • In the periphery, they work by reducing inflammation.

  • In the spine, they decrease presynaptic calcium and sodium influx, production and release of excitatory amino acids, such as substance P, and postsynaptic excitability.

Anticonvulsants Inhibit high-frequency neuronal firing by blocking sodium channels and reducing neuron hyperexcitability.
NMDA-receptor antagonists (ketamine) Bind to the NMDA receptor, thereby inhibiting glutamate activation. Glutamate is an excitatory amino acid found in laminae I, II, and III of the dorsal horn of the spinal cord, where it activates primary afferent neurons.
Alpha-2 adrenergic agonists Act on the descending pain pathways supra-spinally, activating receptors to stimulate acetylcholine release, and on the ascending pain pathways, by inhibiting substance P release from the primary afferent neurons, thus reducing transmission of pain.
Antidepressants Alter neurotransmitters that affect pain pathways by inhibiting presynaptic neuronal reuptake of serotonin and norepinephrine at the descending pain pathway, resulting in improved inhibition of pain.

Table 1.

Mechanism of action of different analgesics (elaborated from text in Ref. [3]).

Analgesic combinations are currently recommended by several guidelines and are used in clinical practice [21]. In patients with moderate-to-severe pain, the general recommendation is the combination of opioid and non-opioid analgesics [22]:

  1. Among the possible combinations, paracetamol has been associated with weak (e.g., codeine or tramadol) or strong (e.g., morphine or oxycodone) opioids. Besides being less effective than NSAIDs [23, 24], paracetamol may cause gastrointestinal (GI), cardiovascular (CV), and hepatic adverse effects [25, 26].

  2. NSAID/opioid combinations have the advantage of anti-inflammatory and additive analgesic effect, along with a well-demonstrated opioid-sparing activity [27]. Currently available NSAID/opioid FDCs include:

    • Hydrocodone/ibuprofen (7.5/400 mg) and oxycodone/ibuprofen (5/400 mg) are two oral, fixed-dose combination formulations, approved for the short-term management of acute, moderate-to-severe pain. A single tablet provided better analgesia than low-dose hydrocodone/oxycodone or ibuprofen administered alone, in most trials, and appeared to be more effective than a single dose of some other fixed-dose combination analgesics [28, 29, 30, 31].

    • An FDC of the fast-acting NSAID, dexketoprofen trometamol, and the long-acting opioid, tramadol hydrochloride, have been recently developed to generate multimodal analgesia at lower and better tolerated doses than those of the single agents used alone. The different modes and sites of action of the two components, together with their complementary pharmacokinetic profiles, and the lower incidence of the typical side effects of each class [32, 33, 34, 35] provides physicians with an effective and safe analgesic for the treatment of moderate-to-severe acute pain [36]. This FDC provides a comprehensive multimodal approach for moderate-to-severe acute pain, thanks to the central analgesic effect, peripheral analgesic action, and anti-inflammatory activity [21].


4. Multimodal analgesia: different combinations for different types of pain

Thanks to the possibility to minimize drug dosages optimizing efficacy, multimodal therapy is useful in various medical field, from acute pain management to post-trauma or postsurgical pain treatment, besides control of chronic pain and its exacerbations or reduction of pain associated with post-immobilization rehabilitation [19]. Each type of pain requires a specific analgesic therapy, which should also be personalized according to the patient’s profile. The main applications of multimodal therapy to different pain conditions are the following.

4.1 Musculoskeletal pain (MP)

Given the multiplicity of mechanisms responsible for MP, the combination of analgesics with different mechanisms of action for the relief of acute and chronic skeletal muscle pain is often recommended, with the possible advantage of pharmacokinetic synergy and improved patient adherence.

The main pharmacological associations currently available for the treatment of MP are [19]:

  • codeine 30 mg + paracetamol 500 mg,

  • ibuprofen 150 mg + paracetamol 500 mg,

  • codeine 30 mg + ibuprofen 400 mg,

  • tramadol 37.5 mg + paracetamol 325 mg,

  • tramadol 75 mg + dexketoprofen 25 mg, and

  • oxycodone 5 mg (10 and 20 mg) + paracetamol 325 mg.

For all these combinations, careful monitoring must be performed in order to assess whether continuation of therapy, suspension, or transition to a strong opioid is necessary [19].

4.2 Osteoarthritis (OA) pain

Pain associated with rheumatologic conditions has a strong peripheral nociceptive component, although recent data also suggest a central sensitization [37]. Ideal treatment of rheumatic pain should be through a multimodal approach, integrating non-pharmacologic and pharmacologic treatments [38]. In the context of rheumatological painful conditions, the association of dexketoprofen and tramadol may represent an attractive medication for acute exacerbations of OA pain, due to its pharmacological profile: the combination of dexketoprofen and tramadol, targeting different sites of action, is suitable for OA type of pain, arising from different body structures (joints, muscles, ligaments, etc.) [21]. The rapid onset of analgesic effect of dexketoprofen, with its anti-inflammatory activity, associated to the sustained action of tramadol, makes their combination a valuable tool to achieve multimodal analgesia in OA patients [21].

4.3 Back pain

Back problems are the third reason for seeking medical help, with about 90% of people suffering from them at some point in their lives [39, 40]. Most episodes of back pain are short lasting with little or no consequence, but recurrent episodes are common and back pain is increasingly understood as a long-lasting condition with a variable course rather than episodes of unrelated occurrences [41]. The complexity of chronic back pain management highlights the need for early intervention in patients with acute back pain in order to prevent progression to chronic back pain [42]. Chronic low back pain has been shown to be secondary to both neuropathic and nociceptive pain mechanisms [43]: a multimodal approach is therefore appropriate. The pain treatment armamentarium for both acute and chronic back pain includes NSAIDs, opioids, steroids, topical medicines, and adjuvants: the choice of medication depends on a number of factors, including the duration of symptoms, severity of symptoms, expected benefits, prior response to medications, adverse effect profile, presence of comorbidities, costs, and degree of supporting evidence [44]. Most guidelines endorse (NSAIDs) and weak opioids for short periods when there is contraindication or lack of improvement with NSAIDs [45].

4.4 Fibromyalgia

Fibromyalgia is mainly a centralized pain disorder, accompanied by fatigue, sleep disturbance, and memory and mood difficulties [43]. Effective drugs combinations for this condition include tramadol + paracetamol [46], cyclobenzaprine + fluoxetine [47], pregabalin added to either quetiapine or trazodone [48], and fluoxetine + amitriptyline [49].

4.5 Postsurgical pain

Surgical pain may be nociceptive, neuropathic, mixed, psychogenic, or idiopathic, depending on the surgical procedure. The value of balanced analgesia in treating postoperative pain was recognized by Kehlet and Dahl [9] over two decades ago. Non-opioid analgesics are the cornerstone of postsurgical pain multimodal management: in addition to their opioid-sparing effects, many of these agents are highly effective in reducing postoperative pain and allowing for faster mobilization [50].

  • Many current multimodal protocols include paracetamol [51, 52, 53], based on its opioid-sparing effects, despite the risk of GI, CV, and hepatic adverse events [25, 26].

  • NSAIDs represent another class of medication that is highly effective for perioperative pain management: despite concerns about the increased risk of postoperative bleeding with NSAIDs, a meta-analysis revealed that ketorolac does not increase the risk of perioperative bleeding [54]. Nevertheless, this drug has shown several other side effects. Preoperative COX inhibitors (primarily selective COX-2 inhibitors) [55] and postoperative nonselective and selective NSAIDs [56] have been associated with reduced postoperative opioid consumption [57]. The combination of NSAIDs with opioids represents another tool to limit opioid use: in particular, the combination dexketoprofen/tramadol was shown to be superior vs. single components in terms of control of moderate-to-severe acute pain after abdominal hysterectomy [58] and total hip arthroplasty [59], with a safety profile fully in line with that previously known for the single agents in monotherapy. Recently, the analgesic efficacy of dexketoprofen/tramadol was compared in a head-to-head study (DAVID study) to that of tramadol/paracetamol combination in moderate-to-severe pain following surgical removal of impacted lower third molar, showing the greatest sustained analgesia during the 6-hour post dose period [60].

  • Another class of analgesics commonly used in multimodal analgesic protocols is the gabapentinoids, which include gabapentin and pregabalin. Meta-analyses have demonstrated that gabapentin [61] and pregabalin [62] improve postoperative pain when part of a multimodal regimen but are associated with sedation, particularly in elderly patients.

  • Other agents to consider in multimodal protocols include NMDA antagonists, such as ketamine. Ketamine has a clear opioid-sparing effect in the perioperative period [63] and may reduce long-term opioid consumption in opioid-tolerant patients [64] as well as persistent postsurgical pain when used intravenously [65].

  • Multimodal and preemptive analgesia as part of an ERAS (Enhanced Recovery after Surgery) protocol facilitates early mobility and early return of bowel function and decreases postoperative morbidity [66].

4.6 Neuropathic pain

The International Association for the Study of Pain defines neuropathic pain as “Pain caused by a lesion or disease of the somatosensory system.” This includes central disorders (e.g., spinal cord injury pain, multiple sclerosis pain, and poststroke thalamic pain) as well as peripheral disorders (e.g., diabetic neuropathy and postherpetic neuralgia) [43].

Both tricyclic antidepressants and gabapentinoids are proposed as firstline agents for neuropathic pain [67]. These medications have completely different mechanisms of actions:

  • gabapentinoids are alpha-2-delta calcium channel modulators;

  • tricyclic antidepressants have multiple mechanisms of action, including norepinephrine and serotonin reuptake inhibition, and so are logical candidates for combination therapy.

Opioids and gabapentinoids were also studied for neuropathic pain and the combination was found to be positive [68, 69, 70]. However, given the limited trial size and the short duration of the studies conducted so far, it is not possible to make recommendations for any specific combination for neuropathic pain [43].


5. Conclusions

As illustrated above, in recent years, the WHO ladder approach has gradually been replaced with the multimodal approach, customized from patient to patient taking into account the characteristics of pain (based on pain generator, its cause, type, and intensity) and patient comorbidity. This allows to control not only chronic pain but also its exacerbations, through the association to long-term analgesic therapy of additional drugs for acute pain as needed. In this respect, multimodal therapy represents a useful tool, not only for specialists but for general practitioners as well to personalize analgesic treatment according to the patient’s characteristics and needs [71].

The availability of FDCs of most recommended combinations may help in the implementation of multimodal analgesia in clinical practice, improving patient adherence to treatment and contributing to the optimization of pain management.



The authors are particularly grateful to ContentEdNet for the editorial support. Editing has also been supported by Paolo Procacci Foundation (Via Tacito 7, 00193 Roma, Italy).


Conflict of interest

The authors do not have any potential conflict of interest related to this chapter.


  1. 1. Argoff CE, Albrecht P, Irving G, Rice F. Multimodal analgesia for chronic pain: Rationale and future directions. Pain Medicine. 2009;10(Suppl 2):S53-S66. DOI: 10.1111/j.1526-4637.2009.00669.x
  2. 2. Raffa RB, Pergolizzi JV Jr, Tallarida RJ. The determination and application of fixed-dose analgesic combinations for treating multimodal pain. The Journal of Pain. 2010;11:701-709
  3. 3. Manworren RC. Multimodal pain management and the future of a personalized medicine approach to pain. AORN Journal. 2015;101(3):308-318. DOI: 10.1016/j.aorn.2014.12.009
  4. 4. Busse JW, Wang L, Kamaleldin M, et al. Opioids for chronic noncancer pain: A systematic review and meta-analysis. Journal of the American Medical Association. 2018;320(23):2448-2460. DOI: 10.1001/jama.2018.18472
  5. 5. Breivik H, Gordh T, Butler S. Keeping an open mind: Achieving balance between too liberal and too restrictive prescription of opioids for chronic non-cancer pain: Using a two-edged sword. Scandinavian Journal of Pain. 2012;3(1):1-4. DOI: 10.1016/j.sjpain.2011.11.012
  6. 6. Varrassi G, Müller-Schwefe G, Pergolizzi J, et al. Pharmacological treatment of chronic pain - The need for CHANGE. Current Medical Research and Opinion. 2010;26(5):1231-1245. DOI: 10.1185/03007991003689175
  7. 7. O'Brien T, Christrup LL, Drewes AM, et al. European Pain Federation position paper on appropriate opioid use in chronic pain management. European Journal of Pain. 2017;21(1):3-19. DOI: 10.1002/ejp.970
  8. 8. Breivik H, Eisenberg E, O’Brien T. The individual and societal burden of chronic pain in Europe: The case for strategic prioritisation and action to improve knowledge and availability of appropriate care. BMC Public Health. 2013;13:1229
  9. 9. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesthesia and Analgesia. 1993;77:1048-1056
  10. 10. World Health Organization. Cancer Pain Relief with a Guide to Opioid Availability. 2nd ed. Geneva: World Health Organization; 1996
  11. 11. Dworkin R, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: Evidence based recommendations. Pain. 2007;132:237-251
  12. 12. Raffa RB, Tallarida RJ, Taylor R Jr, Pergolizzi JV Jr. Fixed-dose combinations for emerging treatment of pain. Expert Opinion on Pharmacotherapy. 2012;13(9):1261-1270
  13. 13. Houde R, Wallenstein S, Beaven W. Clinical measurement of pain. In: De Stevens G, editor. Analgesics. New York, NY: Academic Press; 1965. pp. 75-122
  14. 14. Varrassi G. Non-opioid drugs in the potentiation of postoperative analgesia [Farmaci non oppioidi nel potenziamento dell’analgesia postoperatoria]. In: Varrassi G, editor. Atti 11° Congresso Nazionale AISD. Napoli, Italy: Casa Editrice L'Antologia; 1988. pp. 53-70. Available from:
  15. 15. Schug SA, Zech D, Dorr U. Cancer pain management according to WHO analgesic guidelines. Journal of Pain and Symptom Management. 1990;5:27-32
  16. 16. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The Journal of Pain. 2016;17:131-157
  17. 17. Altman RD, Hochberg MC, Moskowitz RW, Schnitzer TJ. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. Arthritis and Rheumatism. 2000;43:1905-1915
  18. 18. O’Brien J, Pergolizzi J, van de Laar M, et al. Fixed-dose combinations at the front line of multimodal pain management: Perspective of the nurse-prescriber. Nursing: Research and Review. 2013;3:9-22
  19. 19. Gigliotti S et al. Management of musculoskeletal pain in the setting of territorial orthopedics. Minerva Ortopedica e Traumatologica. 2020;71(1):23-31
  20. 20. Varrassi G, Alon E, Bagnasco M, et al. Towards an effective and safe treatment of inflammatory pain: A Delphi-guided expert consensus. Advances in Therapy. 2019;36(10):2618-2637. DOI: 10.1007/s12325-019-01053
  21. 21. Varrassi G, Hanna M, Macheras G, et al. Multimodal analgesia in moderate-to-severe pain: A role for a new fixed combination of dexketoprofen and tramadol. Current Medical Research and Opinion. 2017;33(6):1165-1173. DOI: 10.1080/03007995.2017.1310092
  22. 22. Chandanwale AS, Sundar S, Latchoumibady K, et al. Efficacy and safety profile of combination of tramadol-diclofenac versus tramadol- paracetamol in patients with acute musculoskeletal conditions, postoperative pain, and acute flare of osteoarthritis and rheumatoid arthritis: A phase III, 5-day open-label study. Journal of Pain Research. 2014;7:455-463
  23. 23. da Costa BR, Reichenbach S, Keller N, et al. Effectiveness of nonsteroidal anti-inflammatory drugs for the treatment of pain in knee and hip osteoarthritis: A network meta-analysis. Lancet. 2016;387:2093-2105
  24. 24. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safety of paracetamol for spinal pain and osteoarthritis: Systematic review and meta-analysis of randomised placebo controlled trials. BMJ (Clinical Research Edition). 2015;350:h1225
  25. 25. Roberts E, Delgado Nunes V, Buckner S, et al. Paracetamol: Not as safe as we thought? A systematic literature review of observational studies. Annals of the Rheumatic Diseases. 2016;75:552-559
  26. 26. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis – An expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Medicine. 2015;13:55
  27. 27. Varrassi G, Marinangeli F, Agro F, et al. A double-blinded evaluation of propacetamol versus ketorolac in combination with patient-controlled analgesia morphine: Analgesic efficacy and tolerability after gynecologic surgery. Anesthesia and Analgesia. 1999;88:611-616
  28. 28. Kolesnikov YA, Wilson RS, Pasternak GW. The synergistic analgesic interactions between hydrocodone and ibuprofen. Anesthesia and Analgesia. 2003;97:1721-1723
  29. 29. Oldfield V, Perry CM. Oxycodone/ibuprofen combination tablet: A review of its use in the management of acute pain. Drugs. 2005;65:2337-2354
  30. 30. Betancourt JW, Kupp LI, Jasper SJ, et al. Efficacy of ibuprofen hydrocodone for the treatment of postoperative pain after periodontal surgery. Journal of Periodontology. 2004;75:872-876
  31. 31. Van Dyke T, Litkowski LJ, Kiersch TA, et al. Combination oxycodone 5 mg/ibuprofen 400mg for the treatment of postoperative+ pain: A double-blind, placebo- and active-controlled parallelgroup study. Clinical Therapeutics. 2004;26:2003-2014
  32. 32. Rodriguez MJ, Arbos RM, Amaro SR. Dexketoprofen trometamol: Clinical evidence supporting its role as a painkiller. Expert Review of Neurotherapeutics. 2008;8:1625-1640
  33. 33. Scott LJ, Perry CM. Tramadol: A review of its use in perioperative pain. Drugs. 2000;60:139-176
  34. 34. Vazzana M, Andreani T, Fangueiro J, et al. Tramadol hydrochloride: Pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems. Biomedicine & Pharmacotherapy. 2015;70:234-238
  35. 35. Walczak JS. Analgesic properties of dexketoprofen trometamol. Pain Management. 2011;1:409-416
  36. 36. Moore RA, Gay-Escoda C, Figueiredo R, et al. Dexketoprofen/tramadol: Randomised double-blind trial and confirmation of empirical theory of combination analgesics in acute pain. The Journal of Headache and Pain. 2015;16:541
  37. 37. Meeus M, Vervisch S, De Clerck LS, et al. Central sensitization in patients with rheumatoid arthritis: A systematic literature review. Seminars in Arthritis and Rheumatism. 2012;41(4):556-567
  38. 38. Fitzcharles MA et al. Management of chronic pain in the rheumatic diseases with insights for the clinician. Therapeutic Advances in Musculoskeletal Disease. 2011;3:179-190
  39. 39. Sauver St JL et al. Why do patients visit their doctors? Assessing the most prevalent conditions in a define US population. Mayo Clinic Proceedings. 2013;88:56-67
  40. 40. Nasser MJ. How to approach the problem of low back pain: An overview. Journal of Family and Community Medicine. 2005;12:3-9
  41. 41. Hartvigsen J et al. What low back pain is and why we need to pay attention. Lancet. 2018;391:2356-2367
  42. 42. Morlion B. Pharmacotherapy of low back pain: Targeting nociceptive and neuropathic pain components. Current Medical Research and Opinion. 2011;27:11-33
  43. 43. Dale R, Stacey B. Multimodal treatment of chronic pain. The Medical Clinics of North America. 2016;100(1):55-64. DOI: 10.1016/j.mcna.2015.08.012
  44. 44. Chou R. Pharmacological management of low back pain. Drugs. 2010;70:387-402
  45. 45. Oliveira CB et al. Clinical practice guidelines for the management of non specific low back pain in primary care: An updated overview. European Spine Journal. 2018;27:2791-2803
  46. 46. Bennett RM, Kamin M, Karim R, et al. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: A double-blind, randomized, placebo-controlled study. The American Journal of Medicine. 2003;114(7):537-545
  47. 47. Cantini F, Bellandi F, Niccoli L, et al. Fluoxetine combined with cyclobenzaprine in the treatment of fibromyalgia. Minerva Medica. 1994;85(3):97-100. [in Italian]
  48. 48. Calandre EP, Morillas-Arques P, Molina-Barea R, et al. Trazodone plus pregabalin combination in the treatment of fibromyalgia: A two-phase, 24-week, open-label uncontrolled study. BMC Musculoskeletal Disorders. 2011;12:95
  49. 49. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis and Rheumatism. 1996;39(11):1852-1859
  50. 50. Schwenk ES, Mariano ER. Designing the ideal perioperative pain management plan starts with multimodal analgesia. Korean Journal of Anesthesiology. 2018;71(5):345-352. DOI: 10.4097/kja.d.18.00217
  51. 51. Wick CE, Grant MC, Wu CL. Postoperative multimodal analgesia pain management with nonopioid analgesics and techniques a review. JAMA Surgery. 2017;152(7):691-697. DOI: 10.1001/jamasurg.2017.0898
  52. 52. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology. 2005;103:1296-1304
  53. 53. Hebl JR, Dilger JA, Byer DE, Kopp SL, Stevens SR, Pagnano MW, et al. A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Regional Anesthesia and Pain Medicine. 2008;33:510-517
  54. 54. Gobble RM, Hoang HL, Kachniarz B, Orgill DP. Ketorolac does not increase perioperative bleeding: A meta-analysis of randomized controlled trials. Plastic and Reconstructive Surgery. 2014;133:741-755
  55. 55. Nir RR et al. Preoperative preemptive drug administration for acute postoperative pain: A systematic review and metaanalysis. European Journal of Pain. 2016;20(7):1025-1043
  56. 56. Maund E et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: A systematic review. British Journal of Anaesthesia. 2011;106(3):292-297
  57. 57. Polomano RC, Fillman M, Giordano NA, Vallerand AH, Nicely KL, Jungquist CR. Multimodal analgesia for acute postoperative and trauma-related pain. The American Journal of Nursing. 2017;117(3 Suppl 1):S12-S26. DOI: 10.1097/01.NAJ.0000513527.71934.73
  58. 58. Moore RA et al. Dexketoprofen/tramadol 25 mg/75 mg: Randomised double-blind trial in moderate-to- severe acute pain after abdominal hysterectomy. BMC Anesthesiology. 2016;16:9
  59. 59. McQuay HJ et al. Randomized clinical trial of dexketoprofen/tramadol 25mg/75mg in moderate-to-severe pain after total hip arthroplasty. British Journal of Anaesthesia. 2016;116:269-276
  60. 60. Gay-Escoda C et al. Tramadol/dexketoprofen (TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: Results of a randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third molar extraction pain model (DAVID study). BMJ Open. 2019;9:e023715
  61. 61. Hurley RW, Cohen SP, Williams KA, Rowlingson AJ, Wu CL. The analgesic effects of perioperative gabapentin on postoperative pain: A meta-analysis. Regional Anesthesia and Pain Medicine. 2006;31:237-247
  62. 62. Dong J, Li W, Wang Y. The effect of pregabalin on acute postoperative pain in patients undergoing total knee arthroplasty: A meta-analysis. International Journal of Surgery. 2016;34:148-160
  63. 63. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Canadian Journal of Anaesthesia. 2011;58:911-923
  64. 64. Loftus RW, Yeager MP, Clark JA, Brown JR, Abdu WA, Sengupta DK, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113:639-646
  65. 65. McNicol ED, Schumann R, Haroutounian S. A systematic review and meta-analysis of ketamine for the prevention of persistent postsurgical pain. Acta Anaesthesiologica Scandinavica. 2014;58:1199-1213
  66. 66. Simpson JC, Bao X, Agarwala A. Pain management in enhanced recovery after surgery (ERAS) protocols. Clinics in Colon and Rectal Surgery. 2019;32(2):121-128. DOI: 10.1055/s-0038-1676477
  67. 67. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clinic Proceedings. 2010;85(3 Suppl):S3-S14
  68. 68. Gatti A, Sabato AF, Occhioni R, et al. Controlled-release oxycodone and pregabalin in the treatment of neuropathic pain: Results of a multicenter Italian study. European Neurology. 2009;61(3):129-137
  69. 69. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. The New England Journal of Medicine. 2005;352(13):1324-1334
  70. 70. Hanna M, O’Brien C, Wilson MC. Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. European Journal of Pain. 2008;12(6):804-813
  71. 71. Varrassi G, Yeam CT, Rekatsina M, Pergolizzi JV, Zis P, Paladini A. The expanding role of COX inhibitor/opioid receptor agonist combination in the management of pain. Drugs. 04 August 2020. DOI: 10.1007/s40265-020-01369-x

Written By

Antonella Paladini and Giustino Varrassi

Submitted: 28 May 2020 Reviewed: 17 August 2020 Published: 03 September 2020