Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol

Abstract

Background: Untreated and under-treated pain represent one of the most pervasive health problems, which is worsening as the population ages and accrues risk for pain. Multiple treatment options are available, most of which have one mechanism of action, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns. Another limitation of single-agent analgesia is that, in general, pain is due to multiple causes. Combining drugs from different classes, with different and complementary mechanism(s) of action, provides a better opportunity for effective analgesia at reduced doses of individual agents. Therefore, there is a potential reduction of adverse events, often dose-related. Analgesic combinations are recommended by several organizations and are used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer advantages over extemporaneous combinations.

Conclusions: Dexketoprofen/tramadol (25 mg/75 mg) is a new oral fixed-dose combination offering a comprehensive multimodal approach to moderate-to-severe acute pain that encompasses central analgesic action, peripheral analgesic effect and anti-inflammatory activity, together with a good tolerability profile. The analgesic efficacy of dexketoprofen/tramadol combination is complemented by a favorable pharmacokinetic and pharmacodynamic profile, characterized by rapid onset and long duration of action. This has been well documented in both somatic- and visceral-pain human models. This review discusses the available clinical evidence and the future possible applications of dexketoprofen/tramadol fixed-dose combination that may play an important role in the management of moderate-to-severe acute pain.

Keywords:

• Acute pain
• multimodal analgesia
• drug combination
• NSAIDs
• opioids
• dexketoprofen
• tramadol

Introduction

Pain is a global public health issue, and represents the most common reason for both physician consultation and hospital admissions^1,2. When unrelieved or poorly controlled, it is associated with medical complications, poor patient satisfaction, and increased risk of developing chronic pain³. Several studies^4–10 have shown that post-operative pain, not adequately managed, can result in chronic pain. Chronic post-surgical pain (CPSP) is a serious problem. Indeed, an incidence as high as 50% has been reported, depending on type of surgery undergone. Besides biomedical factors (such as pre-operative pain, severe acute post-operative pain, modes of anesthesia, and surgical approaches), psychosocial elements (especially depression, psychological vulnerability, stress, and late return to work) show a likely correlation with CPSP¹¹. Recent studies suggest that CPSP may be prevented thanks to the right post-operative analgesic strategies^12,13.

On a global scale, the impact of pain has far reaching effects upon the social structure, function, and economic welfare of society as a whole. Moreover, the burden of pain has a significant impact on healthcare utilization and labor force participation^14,15. Hence, effective pain control should be a priority that needs to be fully addressed.

Recent years have seen a progressive unraveling of the neuroanatomical circuits and cellular mechanisms underlying pain initiation, including the identification of molecules able to modulate specific neuronal cell types, which could represent novel targets for innovative pain therapies. Major advances have occurred at all levels, spanning from studies investigating pain transduction mechanisms as well as neuronal plasticity to cortical imaging studies, which have revealed how pain is experienced at the cognitive level^16,17. Furthermore, advances in imaging technology provided pain physicians with advanced tools for the diagnosis of different types of pain, and evaluation of its treatments¹⁶.

Current pain management: therapeutic challenges

Despite advances in pain medicine, the management of acute pain appears not to be a priority, and is still poorly addressed. Untreated and under-treated pain represent the most pervasive health problem, that is worsening as the population ages and accrues risk for pain-causing diseases and disorders. Indeed, pain care has not yet achieved the synergy that should be afforded through a comprehensive and integrated approach to research, diagnosis, and treatment of pain¹⁶. Thus, pain management still poses several challenges to all the healthcare professionals. These include deeper appreciation of the complex interplay between peripheral and central nervous systems in pain perception, increased awareness of the multiple mechanisms underlying pain transmission, facilitation and inhibition, as well as a clear identification of the barriers within the global health systems, and among clinicians and healthcare professionals to appropriately assess and manage pain.

Multiple options are currently available for pain management, most of which have predominantly mono-modal mechanisms of analgesic action¹⁸, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns¹⁹. Therefore, the optimal strategy for treating this multifaceted medical condition is one that uses a combination of drugs that acts through multiple modes and sites of action to the therapeutic end-point, i.e. analgesia¹⁸. Combining drugs with different mechanisms and sites of action would yield a better pain relief, with the fewest side-effects¹⁸. This concept is widely accepted in the literature. At the beginning, it was pharmacologically studied in the 1960s by Houde et al.²⁰, then clinically suggested (especially in post-operative pain) in the 1980s²¹, and a few years later very much diffused by Kehlet and Dahl²², who were talking of “multimodal” analgesia. More recently, the “multimodal analgesia” has been deeply studied also to see whether the drugs used together may be simply additive or synergistic²³, do well in single-dose analgesic studies²⁴, and offer several benefits, including a broader spectrum of action, greater efficacy, better compliance, and a better efficacy/safety ratio²⁵. As a result, analgesic combinations are recommended by the World Health Organization (WHO), American Pain Society (APS), and American College of Rheumatology (ACR)^26–29, and are commonly used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer additional advantages over extemporaneous combinations, including ease of administration, reduction of pill burden, and/or requirement for lower dosages of the individual components³⁰.

Analgesic drug combinations

In patients with moderate-to-severe pain the general recommendation is the combination of opioid/non-opioid analgesics, based on the increasing pain severity³¹. A number of analgesic drug combinations have been tested for the management of post-operative pain, including paracetamol with weak (e.g. codeine or tramadol) or strong (e.g. morphine or oxycodone) opioids. Besides being less effective than NSAIDs^32,33, paracetamol may not be as safe as originally believed, both from a gastrointestinal (GI) and cardiovascular (CV) perspective, not to mention the well-known hepatotoxicity (especially at doses higher than 3 g daily)^34,35. Despite adding codeine to paracetamol producing worthwhile additional pain relief³⁶, none of the available studies found this combination to be superior to NSAIDs in controlling post-operative pain³⁷. Combining an effective NSAID with an opioid could represent, therefore, a better alternative. NSAID/opioid combinations have the advantage of additive analgesic effect, along with a low dose of opioids and, hence, minimal undesirable adverse effects³¹. In addition, NSAIDs display a well demonstrated opioid-sparing activity³⁸, allowing a significant opioid dose reduction as well as a significant reduction in nausea, post-operative nausea and vomiting, and potential respiratory depression, always possible at the end of surgery; an effect not observed with selective COX-2 inhibitors or paracetamol³⁹.

The success of a drug combination depends on the proper selection of both the NSAID and the opioid, as well as of the most appropriate ratio for their combination. Given these indices, the resultant medications should provide an enhanced analgesic efficacy and safety, compared with the single drugs administered in monotherapy.

Currently available NSAID-opioid fixed-dose combinations

Hydrocodone/ibuprofen (7.5 mg/400 mg) and Oxycodone/ibuprofen (5 mg/400 mg) are two oral, fixed-dose combination formulations. They are approved in the US for the short-term (up to 7 days) 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. While co-administration of ibuprofen and hydrocodone/oxycodone in experimental models produces synergistic analgesia^40,41, clinical trials in patients submitted to oral surgery showed only an additive effect^42,43. Nausea, dizziness, and somnolence were the treatment-related adverse events that occurred most frequently after a single dose or multiple doses.

A fixed dose combination (FDC) of the fast acting NSAID, dexketoprofen trometamol, and the long acting opioid, tramadol hydrochloride, has been recently developed to generate multimodal analgesia at lower and better tolerated doses than those of the single agents used alone. The rationale for developing an oral FDC of dexketoprofen 25 mg and tramadol 75 mg (referred to as DKP/TRAM FDC) lies in their different modes and sites of action, their complementary pharmacokinetic profiles, and the lower incidence of the typical side-effects of each class^44–47, providing physicians with an effective and safe analgesic for the treatment of moderate-to-severe acute pain⁴⁸.

Unique pharmacological features of dexketoprofen and tramadol

NSAIDs are very effective drugs, and are widely used for acute and chronic pain^49,50, but their use is associated with a broad spectrum of adverse reactions involving GI, liver, kidney, CV system, and skin^51–53. Different attempts have been made to reduce NSAID-induced gastro-duodenal damage⁵³. These include enteric-coated preparations or soluble formulations of NSAIDs, buffered preparations, non-acidic pro-drugs, and the development of enantiomers. The chiral switch of NSAIDs proved to be a rational approach to improve both the efficacy⁵⁴ and safety⁵⁵ of this class of drugs.

While inhibition of prostanoid synthesis remains an important analgesic mode of action for NSAIDs, both in the periphery and the central nervous system (CNS), other mechanisms should be considered⁵⁶. Some NSAIDs, in addition to their effects on prostanoid synthesis, also affect the synthesis and activity of other neuroactive substances, believed to have key roles in processing nociceptive input within the dorsal horn⁵⁷. It has been argued that these other actions, in conjunction with COX inhibition, may synergistically augment the effects of NSAIDs on spinal nociceptive processing. When the clinical efficacy of NSAIDs in dental pain is plotted against the ratio between anti-inflammatory and analgesic activities in experimental models, ketoprofen appears to be the most effective analgesic amongst the different NSAIDs (Figure 1)⁵⁶. Along the same lines, a recent meta-analysis of 13 randomized controlled trials (RCTs) involving 898 patients⁵⁸ found that the efficacy of oral ketoprofen in relieving moderate-to-severe pain was significantly better than that achieved with ibuprofen and/or diclofenac.

Figure 1. Correlation between NSAID anti-inflammatory/analgesic potency ratio in experimental models and clinical analgesic activity in a model of post-surgical dental pain. Graphical elaboration from Cashman⁵⁶.

Dexketoprofen is an anti-inflammatory and analgesic drug inhibiting COX1 and COX2⁴⁷, and appears to be as effective as the double dose of the racemic ketoprofen, but with a faster onset of analgesia^47,59,60. Compared with the free drug, dexketoprofen trometamol has an increased bioavailability accelerating the onset of the therapeutic effect, with a t_max between 0.25–0.75 h⁴⁴, thus ensuring rapid pain relief, an important feature for the treatment of acute pain episodes. Dexketoprofen trometamol is an effective analgesic to relieve pain in the acute symptomatic period and its use has been shown as beneficial in a wide range of clinical conditions⁴⁴. A systematic review of the clinical studies concluded that dexketoprofen is at least as effective as other NSAIDs or paracetamol/opioid combinations⁶⁰. For instance, analgesic efficacy of oral dexketoprofen trometamol is similar to that of ibuprofen in patients with moderate-to-severe dental pain, with a shorter time to onset of analgesia⁶¹.

Dexketoprofen efficacy and rapid onset of analgesic activity⁴⁴ is complemented by a safety profile that favors dexketoprofen over many other NSAIDs. In fact, its administration is associated with a lower risk of GI bleeding compared to rofecoxib and meloxicam^44,47, and this is particularly relevant in the post-operative setting⁴⁴. However, it is worthwhile to emphasize that gastroprotection is mandatory in patients holding one or more GI risk factors^35,52,53. Data from clinical trials showed that dexketoprofen trometamol is well tolerated, and its adverse event profile appears similar to that of the new generation of NSAIDs⁴⁷. Thus, dexketoprofen trometamol is an excellent example that chiral switch of NSAIDs, shown to be a rational approach to improve both the efficacy⁵⁴ and safety of NSAIDs⁵⁵.

Opioid therapy continues to be an important “mainstream” option for the relief of pain, despite continued debate over the efficacy and safety of the use of opioids in chronic non-cancer pain^62–66. Tramadol hydrochloride is an analgesic with a dual mode of action: opioid receptor activation (with high affinity for μ-receptors) and inhibition of monoamine re-uptake^45,46 (Table 1), and offers a suitable alternative, since these two complementary actions are synergistic, enhancing its analgesic effects and improving its tolerability profile. The dual mode of action may be a reflection of the actions of the two enantiomers that form the racemic mixture of tramadol, with the (+) enantiomer showing higher affinity for μ-receptors and being a more effective inhibitor of serotonin, while the (–) enantiomer is a more effective inhibitor of noradrenaline re-uptake⁴⁵. Opioid and non-opioid mechanisms of tramadol are thought to act synergistically on descending inhibitory pathways in the CNS, resulting in the modulation of second order neurons in the spinal cord. Moreover, tramadol inhibition of monoamine re-uptake augments the chemical signal of the descending pain inhibitory pathways, while decreasing the ascending pain impulse. In humans, the central analgesic effect of tramadol is only partially reversed by the opioid antagonist naloxone, thus confirming the involvement of non-opioid mechanisms in its pain-relieving activity⁶⁷. Compared with codeine (which is a pro-drug), tramadol is an active compound with active metabolites (Table 2)^68,69.

Table 1. Summary of the pharmacodynamic features of the opiod agonists, usually combined with non-opioid analgesics.

Drug	Opioid receptor selectivity			Additional mechanisms(s)
	μ	κ	δ
Weak opioids
Codeine	+	+	–	None
Tramadol	+	+	–	5-HT & NA re-uptake inhibition
Strong opioids
Morphine	+++	++	+	None
Oxycodone	++	+++	+	None

Table 2. Summary of the pharmacokinetic features of the opiod agonists, usually combined with non-opioid analgesics.

Drug	Bioavailability (%)	Protein binding	Half-life (h)	Hepatic catabolism	Active metabolite (s)
Weak opioids
Codeine (Inactive pro-drug)	40–70	90	2–3	CYP2D6 Glucuronidation	Morphine (10%) Norcodeine, C6-G
Tramadol (Active drug)	68–72	20	5–6	CYP2D6	O-dimethyltramadol
Strong opioids
Morphine	20–30	20–36	2–4	Glucuronidation	M-3-G M-6-G
Oxycodone	60–80	45	2–3	CYP3A4 CYP2D6	Noroxycodone Oxymorphone

All four compounds are excreted mainly by the renal route.

Tramadol efficacy for the management of moderate-to-severe pain has been demonstrated both in inpatients and day surgery patients, and was found to be comparable to that achieved using equi-analgesic doses of parenteral morphine or alfentanil⁴⁵. Tramadol analgesic efficacy is complemented by a long duration of action (t_1/2 ∼ 6 h) and by a safety profile that favors tramadol over other opioids. Indeed, tramadol has no relevant effects on CV and pulmonary parameters, causes less constipation and opioid-induced bowel dysfunction, and has a low addiction rate^45,46.

Tramadol analgesic efficacy can further be improved by combination with a non-opioid analgesic⁴⁵. Pre-clinical studies in models of nociception^70–73 provided first evidence of the analgesic synergism between tramadol and dexketoprofen, and supported the general premise of interaction between drugs with a different mechanism of action⁷³. Moreover, the anti-nociceptive effect of the combination occurred at doses lower than those necessary for each drug alone to produce comparable effects⁷⁰, while the dose ratio corresponding to synergism was identified as dexketoprofen/tramadol 1:3^72,73. Opioid-induced bowel dysfunction is common, and represents a significant barrier to achieving optimal pain management⁷⁴. Animal studies suggested that NSAIDs—when combined with tramadol—may limit constipation⁷⁵. Accordingly, dexketoprofen was found to be able to counteract tramadol-induced inhibition of GI transit⁷². It is worthwhile mentioning that constipation represents an adverse effect of tramadol less frequently than for other opioids, when given alone⁴⁵. In patients receiving paracetamol-tramadol combination, the incidence of constipation was almost half that observed with paracetamol-codeine combination⁷⁶. A Phase I study in healthy volunteers showed that the relevant pharmacokinetic parameters of dexketoprofen and of tramadol remain virtually identical when these two compounds are administered together, showing the lack of drug-to-drug PK interaction⁷⁷.

Pharmacodynamic profile of dexketoprofen/tramadol FDC

Pre-trial calculations and a dose-finding study⁴⁸ selected an optimal combination of doses of dexketoprofen and tramadol, i.e. 25 mg for the former and 75 mg for the latter, thus confirming that the 1:3 ratio leads to analgesic synergism (Figure 2). Three different but complementary mechanisms of action contribute to DKP/TRAM FDC multimodal analgesia (Figure 3):

Figure 2. Clinical study in a dental pain model showing the best analgesic efficacy of the dexketoprofen-tramadol combination in a 1:3 ratio. Percentage of patients showing response (≥ 50% max TOTPAR) over 6 h post-dose (Primary end-point). Maximum TOTPAR corresponds to the theoretical maximum possible time-weighted sum of the PAR scores, measured on a 5-point VRS (0 = none to 4 = complete). Graphical elaboration from Moore et al.⁴⁸

Figure 3. Fixed-dose combination dexketoprofen/tramadol mechanism of action. Different modes of action contribute to dexketoprofen/tramadol analgesic FDC efficacy. A synergy between central analgesic action, peripheral analgesic effect, and anti-inflammatory activity underlies the multimodal analgesia provided by the fixed-dose combination dexketoprofen/tramadol. 5-HT: 5-hydroxytryptamine (serotonin); AA: arachidonic acid; COX: cyclo-oxygenase; GABA: γ-amino-butyric acid; MOR: μ-opioid receptor; NA: noradrenaline; PG: prostaglandin.

• the analgesic (and anti-inflammatory) action of dexketoprofen, and its central action⁵⁷;

• the opioid receptor activation by tramadol, and

• the indirect activation of central descending monoaminergic pathways by tramadol, with consequent inhibition of the nociceptive transmission to the brain.

Thus, DKP/TRAM FDC is expected to result in a balanced peripheral and central analgesia, along with an anti-inflammatory action⁷⁸, and to meet the most recent guidelines on the management of acute post-operative pain²⁷. At least an additive if not a synergistic effect of this combination is anticipated to result in a tramadol-sparing effect, and accordingly DKP/TRAM FDC contains a dose of tramadol lower than that recommended on its own for the treatment of severe acute pain. In the DKP/TRAM FDC, the rapid onset of the analgesic effect of dexketoprofen is complemented by the prolonged duration of action of tramadol⁷⁸.

In summary, the combination of dexketoprofen and tramadol is rational from both pharmacokinetic and pharmacodynamic standpoints. Also, indeed, phase II and III studies showed a superior analgesic efficacy of the DKP/TRAM FDC over dexketoprofen and tramadol monotherapy in different models of post-surgical pain^48,78,79, providing evidence for its clinical use.

Dexketoprofen/tramadol FDC in the management of acute, moderate-to-severe pain: efficacy and safety in clinical trials

The DKP/TRAM FDC was approved in Europe with a decentralized procedure on January 2016, and it is under registration in many other extra-European countries. The DKP/TRAM FDC is indicated for the short-term symptomatic treatment of moderate-to-severe acute pain on the evidence of its analgesic efficacy in three well established human models⁸⁰, such as third mandibular molar tooth extraction⁴⁸, soft tissue surgeries (STS)⁷⁸, and joint replacement surgery⁷⁹, involving some 1,900 patients with moderate-to-severe acute pain.

In 606 patients undergoing third molar tooth extraction, the administration of DKP/TRAM FDC provided a higher response rate (≥50% max total pain relief, TOTPAR) over the 6 h post-dose compared to that achieved by dexketoprofen 25 mg and tramadol 75 mg⁴⁸. DKP/TRAM FDC exhibited the highest relative risk reduction (RRR), the lowest number needed to treat (NNT = 1.6), and offered the greatest pain relief, lasting up to 8 h. Importantly, patients receiving DKP/TRAM FDC needed less rescue medications. They also had the longest time to re-medication (8 h vs 1.4 h in the placebo receiving patients), and reported the highest scores of patient global evaluation (PGE). Currently, these figures were comparable or even better than those of most other oral treatments for acute pain²⁴.

Abdominal hysterectomy is an example of soft tissue surgeries (STS), and it is one of the procedures most frequently associated to pain in the gynecological population^80,81. In 606 patients submitted to abdominal hysterectomy for benign conditions, the analgesic efficacy of DKP/TRAM FDC was assessed both in single-dose (8 h post-dose) and multiple-dose doses (6 consecutive doses) within a 3-days treatment period. At rest, pain relief provided by the DKP/TRAM FDC was superior to that achieved by monotherapy after both single-dose (measured as Summed Pain Intensity Differences at 8 h - SPID_8,) and multiple-dose (measured as mean pain intensity on a VAS scale) treatment. Similar results were seen for mean pain intensity on movement over 48 h⁷⁸. Like the oral surgery trial, the DKP/TRAM FDC was statistically superior to each single component in terms of percentage of responders and PGE scores. Here again, the percentage of patients using rescue medication over 24 h was significantly lower with the FDC than with dexketoprofen or tramadol. In addition, the overall time to first use of rescue medication was longer on DKP/TRAM FDC compared with each single agent⁷⁸.

Total hip arthroplasty (THA) is an example of joint replacement surgery that has been shown to improve long-term quality-of-life^80,82. It has been regarded as the surgical intervention with greatest improvement in pain and physical function⁷⁹. In 641 patients undergoing primary, unilateral THA, the ability of DKP/TRAM FDC to provide pain relief both at rest and on movement was investigated after single (8-h post-dose) and in multiple-dose (12 consecutive doses) treatment during a 5-days period. The DKP/TRAM FDC showed superior and sustained efficacy in pain control vs the single agents at the same (i.e. dexketoprofen 25 mg) or at higher dose (i.e. tramadol 100 mg). The highest value of SPID₈ was reported in patients receiving the DKP/TRAM FDC, 77% of whom were responders (mean pain intensity VAS score <40) 8 h after the single dose. Furthermore, the analysis of pain intensity scores and mean SPID values at rest from the 3–4 h time point onwards confirmed the superiority of the DKP/TRAM FDC over the single components. Analysis of pain intensity scores at rest during the multiple-dose phase study demonstrated the superior analgesic effect throughout 48 h. In line with the findings from the other clinical trials^48,78, patients receiving DKP/TRAM FDC experienced longer time to first use of rescue medication. Since early mobilization is crucial after hip arthroplasty, pain on movement was also investigated on days 2 and 3. Mean scores for worst pain on movement were slightly lower in DKP/TRAM-treated patients compared to those receiving the single agents⁷⁹.

The DKP/TRAM FDC combines two drugs with known tolerability profiles and, accordingly, safety data stemming from clinical trials are consistent with those previously reported for dexketoprofen and tramadol, when used alone. The incidence of adverse drug reactions (ADRs) was lower with the FDC than with dexketoprofen (25 mg) and tramadol (100 mg), the most frequent ADRs being nausea, vomiting, and dizziness^48,78,79. Moreover, no marked differences in safety outcomes including heart rate, blood pressure, and physical examination were detected.

In conclusion, DKP/TRAM FDC treatment provides effective multimodal analgesia with a good tolerability profile. DKP/TRAM FDC-based therapy is associated with higher percentages of patients experiencing pain relief of short onset, lesser need of rescue medication (Table 3) and higher PGE scores^48,78,79. The increased clinical benefits of this combination are not accompanied by an increase in the number and/or severity of adverse events.

Table 3. Percentage of pain intensity (PI) responders (achievement of mean pain intensity VAS <40 mm) at rest over the first 8 h and percentage of patients using rescue medication (RM) over 24 h, during the multiple dose phase in clinical trials with DKP/TRAM FDC.

	FDC DKP/TRAM	DKP 25 mg	TRAM 100 mg	p-value
Pain after hysterectomy
Percentage of PI responders (mean PI-VAS <40)	65	46	41	.001 vs DKP <.001 vs TRAM
Percentage of patients using RM over 24h	4.4	11	10	.01 vs DKP .021 vs TRAM
Pain after total hip arthroplasty
Percentage of PI responders (mean PI-VAS <40)	77	67	66	.055 vs DKP .029 vs TRAM
Percentage of patients using RM over 24h	7.0	17	19	<.001 vs DKP <.001 vs TRAM

Data from DKP/TRAM FDC clinical trials^78,79.

DKP/TRAM FDC: from clinical trials to clinical practice

The unique pharmacodynamic and pharmacokinetic profile makes the DKP/TRAM FDC an attractive option for adequate management of different painful conditions. Even in high resource countries, pain management in patients undergoing surgery is sub-optimal, with ∼50% of patients reporting pain intensity >4 on the first post-operative day (NRS 0–10)^83,84. Specific areas of improvement in post-operative pain management include the so-called small surgeries with under-estimated levels of pain, like appendectomies⁸⁵. Multimodal analgesia (achieved by the combination of opioid and non-opioid analgesics) remains the most widespread approach to treat acute post-operative pain, as recommended by the recent APS guidelines²⁷. In this connection, the clinical potential of DKP/TRAM FDC is large, and can be effective in minor day case surgeries as well as major surgeries, when the oral route (or the switch to it) is feasible. Its use may also be envisaged for minor surgeries with spinal or regional blocks, such as bunionectomy, rotator cuff repair, as well as for the treatment of breakthrough episodes of pain. Its efficacy in controlling post-operative pain after total hip and knee replacement will allow early patient mobilization, lowering thromboembolic risk, shortening hospitalization, and timely starting of rehabilitation⁸⁶.

Low back pain and osteoarthritis are highly prevalent in the general population⁸⁷, and their therapeutic management should be flexible^88–90 and address the different patterns of pain trajectories (continuous pain along with acute flares) that characterize them. Moreover, pain intensity is dependent on time and exercise⁹¹. DKP/TRAM FDC represents an attractive medication for acute exacerbations of osteoarticular (OA) pain due to its pharmacological profile. OA pain is a mixed phenomenon, where nociceptive and neuropathic mechanisms are involved in both the local and central levels and may present with different clinical features: constant and intermittent pain, with or without a neuropathic component, and with or without central sensitization^92,93. There is a wealth of literature showing the analgesic efficacy of dexketoprofen^94–96 and tramadol^97–99, either single or multiple dosing regimens, in both osteoarthritis and low back pain. Their combination, targeting different sites of action, is, therefore, suitable for this mixed type of pain, arising from different body structures (joints, muscles, ligaments, etc.).

Rehabilitation (exercise and strength training) is widely recommended by international guidelines for managing OA pain¹⁰⁰, and is even considered by 2014 OARSI guidelines¹⁰¹ as the core treatment for all patients. Joint mobilization, however, may trigger or increase pain, and often discourage patients from continuing training programs; in this context, the DKP/TRAM FDC could be useful to relieve movement-related acute pain and allow proper rehabilitation.

Conclusions

A fixed-dose combination of dexketoprofen (25 mg) and tramadol (75 mg) (DKP/TRAM 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^27,78,79. Together with an effective analgesic efficacy, the combination shows a good tolerability profile^48,78,79. A very recent Cochrane review¹⁰² concluded that “A single oral dose of dexketoprofen 25 mg plus tramadol 75 mg provided good levels of pain relief with long duration of action to more people than the same dose of dexketoprofen or tramadol alone”. On the grounds of its efficacy and safety, this medication, which results from the combination of two drugs that have stood the test of time, should be considered as a useful addition to our therapeutic armamentarium against pain.

Transparency

Declaration of funding

This work was carried out thanks to an unrestricted educational grant from MENARINI International.

Declaration of financial/other relationships

MENARINI did not have any role in design, planning, or execution of the review. The terms of the financial support from MENARINI included freedom for the authors to reach their own conclusions, and an absolute right to publish the results of this work, irrespective of any conclusions reached. WM reports personal fees from Menarini, during the conduct of the study; grants and personal fees from Grunenthal, Mundipharma, AcelRx Pharmaceuticals, BioQPharma, and Medicine Company, outside the submitted work. MH, GM, A. Montes, A. Montero, SP, CS, and GV are members of the Scientific Advisory Board and of the Speakers’ Bureau of MENARINI International. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

We are indebted to Chiara Degirolamo, PhD (Letscom SRL, Scientific Division, Rome) for her invaluable help during the preparation of this manuscript.