Pain is a health issue affecting all populations, regardless of age, gender, economic status, race, or geography. Acute pain is the most common type of pain, with a complex aetiology. Inadequately managed acute pain adversely affects quality of life and imposes significant economic burden. The majority of the available pain-relieving drugs have monomodal mechanisms of analgesia, which necessitates combining drugs with non-redundant mechanisms of action in order to provide adequate pain relief and reduce the side effects from higher doses of individual drugs.
In this regard, combining an oral opioid such as codeine or tramadol and a non-opioid such as paracetamol or non-steroidal anti-inflammatory drug offers a plausible option. Pain is a public health issue worldwide and remains the most common cause for physician consultation and hospital admission [ 2 ]. Pain affects all populations, regardless of age, gender, economic status, race, or geography [ 2 ]. Acute pain is the most common type of pain, and can occur due to injury, acute illness, surgery, or arthritis, making its aetiology a complex and transdisciplinary affair [ 2 , 3 ].
Acute flare-ups of rheumatoid arthritis and osteoarthritis are significant contributors to the burden of acute pain in India. Inadequately managed acute pain adversely affects quality of life, physical function, and functional recovery [ 10 , 11 ]. Moreover, inadequately managed pain leads to significant economic burden in terms of healthcare utilisation and labour force participation [ 12 , 13 ].
Despite recent advances in the understanding of the cellular mechanisms underlying pain initiation, including the discovery of novel molecular targets, the management of acute pain remains suboptimal in the majority of patients [ 14 , 15 , 16 , 17 , 18 ]. Consequently, there is an unmet need to identify and address the barriers to appropriate management of acute pain [ 18 ].
This could be addressed in part with increased appreciation of the complex interplay between the peripheral and central nervous systems in pain transmission, facilitation, and inhibition [ 18 ].
The current armamentarium for pain management comprises multiple options, the majority based on monomodal mechanisms of analgesia [ 19 , 20 ]. However, acute pain is multidimensional in nature, involving sensory, affective, cognitive, and behavioural aspects.
Therefore, achieving adequate pain control with a single drug may not be beneficial [ 19 , 20 ]. Moreover, most analgesics exhibit a ceiling of efficacy and have significant safety concerns [ 21 ].
An optimal approach to multimodal pain management might be to combine drugs with non-redundant mechanisms of action that would provide adequate pain relief and also reduce side effects.
Emerging evidence shows additive or synergistic actions of multimodal analgesia in various combinations of analgesic agents [ 22 ]. A line of evidence shows that the combination of opioids and non-steroidal anti-inflammatory drugs NSAIDs improves efficacy and reduces the dose of individual drugs when compared with monotherapy [ 22 , 24 , 25 , 26 ].
Decreased pill burden, greater ease of administration, and the need for lower dosages of individual drug components are key benefits offered by fixed-dose combination FDC analgesics.
Combining oral opioids such as codeine or tramadol and non-opioids such as paracetamol or NSAIDs offers a more suitable option [ 27 ]. Among the currently available FDCs, paracetamol is the most commonly used non-opioid agent.
In addition to the known hepatotoxic potential of paracetamol, its cardiovascular and gastrointestinal GI risk has been a recent cause for concern [ 28 , 29 ]. Paracetamol also lacks the anti-inflammatory effect that is observed predominantly with NSAIDs [ 30 ]. Due to the opioid-sparing action of NSAIDs, the combination of these two drugs significantly reduces opioid dose and mitigates the incidence of adverse events AEs such as nausea, vomiting, and respiratory depression.
For an effective analgesic combination, the selection of the right NSAID and opioid agent at optimal doses is essential. A combination of sustained-release diclofenac and immediate-release tramadol has recently been developed and widely used in clinical practice.
This FDC provides multimodal analgesia at lower and better-tolerated doses than monotherapy with either drug [ 34 , 35 ]. The selected doses are diclofenac 75 mg and tramadol 50 mg. This review outlines the pharmacological properties, clinical efficacy, and tolerability of this FDC combination in adults with acute severe pain. Additional literature was identified from the reference lists of published articles.
Other bibliographic information was also requested from the company manufacturing the drugs. Searches were last updated on 6 December This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
The pharmacodynamic properties of tramadol and diclofenac have been reviewed extensively elsewhere [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. The key pharmacodynamic properties of both of these analgesic agents are described below. Unlike other opioids, tramadol acts primarily on the descending-inhibitory pathway of the central nervous system and inhibits the transmission and perception of pain [ 36 , 38 ].
The synergistic activity associated with the analgesic and anti-nociceptive effects of tramadol is due to the racemic nature of this molecule [ 37 , 38 ]. Besides analgesia, other pharmacological actions of tramadol are similar to opioids, namely constipation, dizziness, sweating, nausea, somnolence, and pruritus.
Unlike other opioid agents, treatment with tramadol is not associated with respiratory and cardiac depression. Further, drug dependence potential is low in patients who are treated with tramadol [ 37 , 38 ]. Unlike morphine, tramadol does not cause histamine release [ 39 , 48 ]. Its mode of action is not well characterised. Although diclofenac is classified as a non-specific COX inhibitor, it is a specific COX-2 isoform inhibitor which effectively inhibits prostaglandin-E2 and thromboxane-A2 synthesis and possesses pro-nociceptive action at peripheral and spinal sites [ 49 , 50 ].
Additionally, diclofenac acts as an eicosanoid oxidoreductase inhibitor and inhibits eicosanoids and lipoxins [ 51 , 52 ]. It also increases plasma-endorphin levels and attenuates N -methyl- d -aspartate NMDA -mediated nociceptive discharge via the l -arginine—nitric oxide—cGMP cyclic guanosine monophosphate pathway [ 49 , 51 , 53 ]. Diclofenac has been shown to reduce prostaglandin and interleukin-6 levels in plasma and synovial fluid in patients with rheumatoid arthritis and osteoarthritis [ 51 , 54 , 55 ].
Compared with other NSAIDs, irrespective of COX-specificity, diclofenac shows greater inhibition of platelet aggregation and acts as a competitive antagonist of thromboxane-prostanoid receptor, signifying potential cardiovascular safety [ 51 , 56 ].
Investigating the pharmacokinetics of this FDC will be of future interest. After oral administration, tramadol is quickly and completely absorbed. Plasma concentration and area under the concentration—time curve AUC increase linearly over a dose range of 50— mg [ 58 ]. It effectively crosses the placental and blood—brain barriers, and small amounts 0. Tramadol achieves peak brain concentration 10 min after oral administration; the corresponding value for active metabolite M1 is 20—60 min [ 58 ].
Following oral administration, tramadol is extensively metabolised in the liver, largely via O - and N -demethylation and conjugation reactions forming glucuronides and sulphates [ 58 ].
Owing to genetic polymorphisms in the gene encoding CYP2D6, tramadol metabolism varies in different phenotypes [ 59 ]. In a study of healthy adult volunteers, those who were poor metabolisers of sparteine, an in vivo probe for CYP2D6 enzyme activity, exhibited significantly higher mean metabolic ratios of tramadol to M1 than extensive metabolisers 4. In young adults, the half-life of tramadol is 5—7 h and the half-life of M1 is 6—8 h [ 57 ]. Diclofenac is well absorbed orally and has a calculated apparent volume of distribution of 0.
The AUC of diclofenac is proportional to the orally administered dose between 25 and mg. Peak concentration in synovial fluid, which is the site of action of NSAIDs, is achieved 2—4 h after attaining peak plasma levels [ 57 ]. Diclofenac binds extensively to plasma proteins Following oral administration, biotransformation of diclofenac is ensured mainly by single and multiple hydroxylation, methoxylation, and partial glucuronidation, resulting in phenolic metabolites which are then converted to glucuronide conjugates.
Total systemic clearance of diclofenac is Elimination from synovial fluid takes around 3—6 h [ 57 ]. The terminal half-life in plasma is 1—2 h [ 30 , 43 , 57 ]. Concurrent use of tramadol and serotonergic medications results in a hyperserotonergic state soon after treatment initiation or changes in the doses of serotonergic medications.
The underlying reason for this effect is the inhibition of metabolic enzymes [ 42 ]. Concomitant use of coumarin derivatives and tramadol may lead to an increased international normalised ratio which may lead to major bleeding and ecchymosis in some patients [ 37 , 57 ]. Co-administration with carbamazepine causes significant increase in tramadol metabolism, presumably through metabolic induction which raises the recommended dose of tramadol [ 58 ].
In vitro studies indicate that diclofenac has no significant effect on the serum protein binding of acenocoumarol, prednisolone, salicylic acid, tolbutamide, or warfarin [ 45 ]. Concomitant administration of antiplatelet medication and anticoagulants with diclofenac could increase the risk of bleeding [ 45 , 57 ].
Diclofenac raises digoxin and methotrexate concentrations, resulting in increased toxicity of these drugs. It also exhibits nephrotoxic and neurological effects when co-administered with cyclosporine and quinolones, respectively [ 57 ]. Like other NSAIDS, diclofenac should be used at the lowest effective dose for the shortest duration to reduce the risk of severe hepatic reactions [ 50 ].
This combination is indicated for symptomatic treatment of severe pain in adults with severe acute pain of trauma, postoperative pain, low back pain, and musculoskeletal pain.
Tramadol is recommended as an important WHO step 2 analgesic and is widely prescribed in clinical practice for the treatment of acute pain, labour pain, and chronic cancer and non-cancer pain [ 65 , 66 ]. The use of tramadol in pain management has increased because of the serious safety issues associated with NSAIDs GI bleeding and COX-2 inhibitors cardiovascular risks, nephrotoxicity , which limit their use in elderly patients and special populations [ 66 ].
Tramadol should be avoided in pregnant women and nursing mothers [ 37 , 57 ]. Caution is warranted when using tramadol in patients with head injury, increased intracranial pressure, and severe impairment of hepatic or renal function, and in patients prone to respiratory depression, addiction, or convulsive disorders [ 57 ]. Diclofenac monotherapy is recommended at the lowest effective dose for the shortest duration of action, and is not recommended in patients with cardiovascular events, myocardial infarction, or stroke [ 57 ].
NSAIDs reportedly cause an increased risk of serious GI adverse events of bleeding, ulceration, and perforation of the stomach or intestine. Local prescribing information should be consulted for information on dosage and administration, contraindications, drug interactions, precautions, and warnings. This combination has complementary modes of action and targets multiple sites, as shown in Fig.
Studies using different dosages and routes of administration for tramadol and diclofenac are also included to illustrate the additive effects of the combination. The key efficacy measures defined here are given in Table 1. The efficacy results are summarised in Fig. The analysis of disease-specific pain scores revealed a similar pattern of pain relief Fig. The study enrolled patients mean age The mean pain score was 9. These results substantiated the findings of the phase III trial.
Severity of pain is an important factor in the selection of analgesic agents by healthcare professionals. Joint pain, traumatic pain, and musculoskeletal conditions are highly prevalent and the most common cause of severe acute pain and physical disability. This has significant clinical relevance, as surgery causes hyperalgesia and allodynia at both local and distal sites [ 34 ]. In another randomised, double-blind, parallel-group study, Mitra et al. This section focuses on tolerability data from the clinical trials discussed above.
Chandanwale et al. Nausea and vomiting are important dose-dependent GI AEs which are associated with tramadol and can be prevented prophylactically by treatment with antiemetic and gastro-protective agents. Shah et al. In this study, five 1.
In a study by Mitra et al. The incidence of nausea and vomiting in this study was comparable to those reported by Smith et al. The study will be conducted in the outpatient hysteroscopy clinic in Cairo university hospitals. All patients attending the outpatient hysteroscopy clinic will be invited to participate in the study. The invitation will include a clear full explanation of the study and patients will provide oral consent. Written informed consent is not needed since the procedure and intervention carries almost no risk to the patient and the patient will not receive anesthesia and will be fully conscious.
Only patients consenting verbally to participate will be included in the trial. Tramadol, diclofenac and placebo will be enclosed in sealed envelopes which will be numbered using computer generated random table. Neither the patient nor the physician will be aware of the drug used. Full history will be taken followed by general and local examination. The procedure will be done in the lithotomy position. Hysteroscopy will be done using a 5mm outer diameter continuous flow hysteroscope with a French working channel and a 30 degrees direction of view provided by Techno GmbH and CO.
The hysteroscope will be introduced using the vaginoscopy technique, in which no speculum will be used. The cervix will be detected and the external os will be identified using the hysteroscope. The hysteroscope will be introduced in the uterine cavity. Saline will be used as the distension medium and the pressure will be set at mm Hg. The anterior wall, posterior wall and tubal ostea will be visualized, any polyps, adhesions septa, congenital malformations or submucous fibroids will be noted.
Base line characteristics and perception of pain will be compared. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies. Hide glossary Glossary Study record managers: refer to the Data Element Definitions if submitting registration or results information.
Search for terms. Save this study. Warning You have reached the maximum number of saved studies Tramadol Versus Diclofenac for Reducing Pain Before Outpatient Hysteroscopy The safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Listing a study does not mean it has been evaluated by the U. Federal Government. Read our disclaimer for details. For analysis, missing scores were replaced by an averaged value calculated from the corresponding time of the day before and after the missing VAS score. Average VAS pain scores for the 14 days did not differ significantly diclofenac group: mean [SD], It is suggested that pain, referred otalgia, and odynophagia after tonsillectomy are caused by inflammation and its mediators, disruption of mucosa, nerve irritation, and spasm of the exposed pharyngeal muscles, with pain lasting for 10 days or longer.
The time to onset of action is 1 hour, the time to peak concentration is 2 hours, and the elimination half-life is 6. Posttonsillectomy analgesia requires a nonsedating, nonrespiratory-depressing analgesic that can be used in an outpatient setting to allow early mobilization and return to regular function.
Opioids do not fit easily with these requirements; they are limited by adverse effects and have monomodal action.
Nonsteroidal anti-inflammatory drugs NSAIDs are nonsedating and nonrespiratory depressing, can be used in outpatients, and are free from the nauseagenic effects of the opioid group. These drugs act by inhibiting tissue prostaglandin production either at the site of injury or centrally, and their extensive use has confirmed that NSAIDs are effective postoperative analgesics, although contraindications and adverse effects limit use.
The common and important adverse effects are impaired platelet function, peptic ulceration, renal dysfunction, and aspirin-induced asthma. We know that the measured bleeding time is extended, but usually not beyond the reference range, 19 an effect caused by reversible inactivation of cyclooxygenase. Long-term treatment with NSAIDs increases the risk of peptic ulceration, but no study documents an increase in gastroduodenal complications within the first week of use, although gastroduodenal mucosal erosions can be demonstrated.
There is a need for an alternative to NSAIDs and opioids for posttonsillectomy analgesia in patients with absolute and relative contraindications. The one previous trial 5 that compared diclofenac monotherapy with tramadol and naproxen combined therapy did not exclude NSAIDs completely from either side of the comparison.
That trial did not determine whether tramadol alone can provide the same analgesic efficacy as NSAIDs. In the trial reported herein, the diclofenac dose was set based on previous experience and is at the upper limit of the recommended range. For tramadol, the recommended dose for moderate pain is 50 to mg 2 to 3 times daily, which is a midrange dose and the dose used in this trial. In conclusion, pain is a significant problem after tonsillectomy.
Various options exist for the management of pain. This study demonstrates that tramadol is as effective as diclofenac for posttonsillectomy pain management. Corresponding author and reprints: Mark J. Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. View Large Download. Clin Otolaryngol. Google Scholar.
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Power IBarratt S Analgesic agents for the postoperative period. Surg Clin North Am. Smith IWilde A Secondary tonsillectomy haemorrhage and non-steroidal anti-inflammatory drugs. Acta Otolaryngol. Kehlet HDahl JB Are perioperative nonsteroidal anti-inflammatory drugs ulcerogenic in the short term? Kenny GNC Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-infammatory drugs. Allerg Immunol Paris.
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