Tramadol Hydrochloride/ Dexketoprofen

Registered South African indications:

• Symptomatic short-term treatment of moderate to severe acute pain in adult patients whose pain is considered to require a combination of tramadol and dexketoprofen

Registered South African contraindications

The contraindications reported for dexketoprofen and tramadol as single medicines, are contraindications for the use of tramadol hydrochloride/ dexketoprofen

Tramadol Hydrochloride/ Dexketoprofen

• Pregnancy
• Breastfeeding

Dexketoprofen

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to any other nonsteroidal anti-inflammatory drug (NSAID)
• Moderate to severe renal impairment (creatinine clearance ≤59ml/min)
• Severely impaired hepatic function (Child-Pugh score 10-15)
• Patients in whom medicines with a similar action (e.g. acetylsalicylic acid, or other NSAIDs) precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause nasal polyps, urticaria or angioedema
• Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates
• Active peptic ulcer/gastrointestinal haemorrhage or any history of gastrointestinal bleeding, ulceration or perforation
• History of gastrointestinal bleeding or perforation, related to previous NSAIDs therapy
• Chronic dyspepsia
• Patients who have other active bleedings or bleeding disorders
• Crohn’s disease or ulcerative colitis
• Severe heart failure
• Haemorrhagic diathesis and other coagulation disorders
• Severe dehydration (caused by vomiting, diarrhoea or insufficient fluid intake)

Tramadol Hydrochloride

• Hypersensitivity to the active ingredient or any of its excipients
• In acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic medicines
• Patients receiving MAO inhibitors, or who have taken them within the last 14 days
• Epilepsy not adequately controlled by treatment
• Severe respiratory depression
• Head injury and a decreased level of consciousness

South African recommendations

Tramadol Hydrochloride/ Dexketoprofen

Caution in the following patient groups

• Mild renal impairment
• Mild to moderate hepatic impairment
• Elderly

Effects on ability to drive and use machines

• The effects known for the single components of tramadol/ dexketoprofen apply to the fixed combination
• Dexketoprofen: May cause dizziness and somnolence which impair the patient’s ability to drive or to use machines
• Tramadol: May cause effects such as somnolence and dizziness and therefore may impair the reactions of drivers and machine operators

Dexketoprofen

Caution in the following patient groups

• History of allergic conditions
• Congenital disorder of porphyrin metabolism (e.g. acute intermittent porphyria)
• Dehydration/hypovolaemia
• Directly after a major surgery
• Haematopoietic disorders
• Systemic lupus erythematosus
• Mixed connective tissue disease

Concomitant nonsteroidal anti-inflammatory drug (NSAID) use

• Avoid concurrent use with other NSAIDs, including COX-2 inhibitors

Dosing and duration

• Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

Gastrointestinal safety

• Gastrointestinal bleeding, ulceration or perforation which can be fatal, have been reported with NSAIDs such as dexketoprofen trometamol at any time during treatment, with or without warning symptoms or a previous history of serious gastrointestinal events. When gastrointestinal bleeding or ulceration occurs in patients receiving dexketoprofen trometamol , the treatment should be withdrawn
• The risk of gastrointestinal bleeding, ulceration or perforation is higher with increasing doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation, and in older people
• Any history of oesophagitis, gastritis and/or peptic ulcer must be sought in order to ensure their total cure before starting treatment
• Patients with gastrointestinal symptoms or history of gastrointestinal disease should be monitored for digestive disturbances, especially gastrointestinal bleeding
• Tramadol hydrochloride/ dexketoprofen, should not be given to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated, see Contraindications
• Patients with a history of gastrointestinal toxicity, particularly when elderly, should report any abdominal symptoms (especially gastrointestinal bleeding) during treatment
• Caution should be advised in patients receiving concomitant medicines which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or antiplatelet medicines such as acetylsalicylic acid

Renal safety

• In patients with renal impairment, tramadol hydrochloride/ dexketoprofen may result in deterioration of renal function, fluid retention and oedema
• Caution is also required in patients receiving diuretic therapy or those who could develop hypovolaemia as there is an increased risk of nephrotoxicity. Adequate fluid intake should be ensured during treatment to prevent dehydration/hypovolaemia
• Tramadol hydrochloride/ dexketoprofen can increase plasma urea and creatinine and is associated with nephrotoxicity which may present as glomerular nephritis, interstitial nephritis, renal papillary necrosis, nephrotic syndrome and acute kidney injury (AKI) (acute renal failure)
• Elderly patients are more likely to be suffering from impaired renal function

Hepatic safety

• Use with caution as tramadol/ dexketoprofen can cause increases in liver function parameters, such as significant increases in aspartate transaminase (AST) also known as serum glutamic oxaloacetic transaminase (SGOT) and alanine transaminase (ALT), also known as serum glutamic-pyruvic transaminase (SGPT)
• Progressive significant increases in liver function parameters indicate deterioration of liver function, necessitating discontinuation of treatment

Cardiovascular and cerebrovascular disease

• Appropriate monitoring and advice are required for patients with a history of hypertension and/or mild to moderate congestive heart failure as fluid retention and oedema have been reported in association with NSAIDs such as contained in tramadol/ dexketoprofen
• Special caution should be exercised in patients with a history of cardiac disease, in particular those with previous episodes of heart failure as there is an increased risk of precipitating heart failure
• Tramadol/ dexketoprofen should not be used in patients with severe cardiac failure
• Clinical trial and epidemiological data suggest that use of some NSAIDs such as contained in this combination product may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). There are insufficient data to exclude such a risk for dexketoprofen
• Patients with uncontrolled hypertension, congestive heart failure, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with tramadol/ dexketoprofen after careful consideration

Haemostasis and coagulation

• Tramadol/ dexketoprofen can inhibit platelet aggregation and prolong bleeding time via inhibition of prostaglandin synthesis. Therefore, its use in patients who are receiving other therapy that interferes with haemostasis, such as warfarin or other coumarins or heparins is not recommended

Severe skin reactions

• Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with the use of NSAIDs, such as contained in tramadol/ dexketoprofen
• Patients appear to be at highest risk of these reactions early in the course of therapy, discontinue at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity

Elderly

• The elderly has an increased frequency of adverse reactions to NSAIDs, such as contained in tramadol/ dexketoprofen especially gastrointestinal bleeding and perforation which may be fatal
• These patients should commence treatment on the lowest dose available. Elderly patients are more likely to be suffering from impaired renal cardiovascular or hepatic function

Hypersensitivity and respiratory conditions

• Severe acute hypersensitivity reactions (e.g. anaphylactic shock) have been observed. Treatment must be discontinued at the first signs of severe hypersensitivity reactions following intake of tramadol/ dexketoprofen
• Patients with asthma combined with chronic rhinitis, chronic sinusitis, and/or nasal polyposis have a higher risk of allergy to acetylsalicylic acid and/or NSAIDs than the rest of the population
• Administration of tramadol/ dexketoprofen can cause asthma attacks or bronchospasm, particularly in subjects allergic to acetylsalicylic acid or NSAIDs

Infections and varicella

• Varicella can be at the origin of serious cutaneous and soft tissues infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of tramadol/ dexketoprofen in case of varicella
• Tramadol/ dexketoprofen can mask the symptoms of infectious diseases. Aggravation of soft tissue infections have been described in temporal connection with the use of NSAIDs, such as contained in tramadol/ dexketoprofen

Paediatric population

• The safety and efficacy of tramadol/ dexketoprofen in children and adolescents <18 years of age have not been established. Therefore tramadol/ dexketoprofen should not be used in children and adolescents <18 years of age

Tramadol

Caution in the following patient groups

• Addicted patients
• Patients with head injury
• Shock
• Reduced level of consciousness of uncertain origin
• Disorders of the respiratory centre or function
• Increased intracranial pressure
• Patients sensitive to opiates

Respiratory depression

• Care should be taken when treating patients with respiratory depression, or if concomitant CNS depressant medicines are being administered, or if the recommended dosage is exceeded as the possibility of respiratory depression cannot be excluded in these situations

Convulsion risk

• Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper daily dose limit (400mg)
• In addition tramadol may increase the seizure risk in patients taking other medicines that lower the seizure threshold
• Patients with a history of epilepsy or those susceptible to seizures should only be treated with tramadol if there are compelling circumstances, see Contraindications

Substance abuse or dependence

• Tolerance, psychic and physical addiction may develop with the use of tramadol/ dexketoprofen. There is an increased risk of addiction in patients with a personal or family history of substance abuse or mental health disorders
• In patients with a tendency to drug abuse or dependence, treatment with tramadol/ dexketoprofen should only be carried out for short periods under strict medical supervision. Tramadol/ dexketoprofen has a maximum treatment duration of 5 days

Risk from concomitant use of sedative medicines such as benzodiazepines or related medicines

• Concomitant use of tramadol/ dexketoprofen and sedative medicines such as benzodiazepines or related medicines may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible
• If a decision is made to prescribe tramadol/ dexketoprofen concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible
• The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms

CYP2D6 metabolism

• Tramadol as contained in tramadol/ dexketoprofen, is metabolised by the liver enzyme CYP2D6. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect may not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency
• However, if the patient is an ultra-rapid metaboliser there is a risk of developing of opioid toxicity even at commonly prescribed doses. Symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite
• In severe cases this may include symptoms of circulatory and respiratory depression, which may be life threatening and fatal
• The prevalence of ultra-rapid metabolisers varies across populations, being higher in certain groups such as African/Ethiopian populations and lower in others, including Asian and Northern European populations

Use in children

• There have been reports in the published literature that tramadol given post-operatively to children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, or in any child with compromised respiratory function from any cause, led to life-threatening adverse events
• Tramadol/ dexketoprofen is not for use in children or adolescents under 18 years of age

Sodium content

• Tramadol/ dexketoprofen contains less than 1mmol sodium (23mg) per dose, i.e. essentially “sodium-free”

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Symptomatic short-term treatment of moderate to severe acute pain in patients whose pain is considered to require a combination of tramadol and dexketoprofen

Tramadol Hydrochloride/ Dexketoprofen
75/25 (mg)

• Oral (fct): 1 tab, daily; Additional doses can be taken as needed, with a minimum dosing interval of 8hrs; Max: 3 tab (225mg tramadol hydrochloride/ 75mg dexketoprofen)/24hrs; Intended for short-term use only and the treatment must be strictly limited to the symptomatic period: Max. treatment duration: 5 days

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Switching to a single component medicine for analgesia should be considered according to pain intensity and response of the patient

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Undesirable effects may be minimised by using the lowest number of doses for the shortest duration necessary to control symptoms

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Method of administration: Swallow with a sufficient amount of fluid (e.g. one glass of water) at least 30 minutes before a meal as concomitant administration with food delays the absorption rate of tramadol/ dexketoprofen

Not established for children below 18 years

Pregnancy

South African recommendations

• Contraindicated

Dexketoprofen

• Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/ foetal development
• Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%
• In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo- foetal lethality
• In addition, increased incidences of various malformations including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period
• During the third trimester of pregnancy, tramadol/ dexketoprofen may expose the foetus to:
  • cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
  • renal dysfunction, which may progress to renal failure with oligohydramnios;
• At the end of pregnancy, the mother and the neonate may be exposed to:
  • possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
  • inhibition of uterine contractions resulting in delayed or prolonged labour

Tramadol

• Animal studies with tramadol as contained in tramadol/ dexketoprofen revealed at high doses effects on organ development, ossification and neonatal mortality
• Teratogenic effects were not observed. Tramadol crosses the placenta and may induce respiratory depression in the neonate
• Chronic use during pregnancy may lead to neonatal withdrawal symptoms

Breastfeeding

South African recommendations

• Contraindicated

Dexketoprofen

• It is not known whether dexketoprofen is excreted in human milk

Tramadol

• Tramadol and its metabolites are found in human breast milk. For this reason, tramadol should not be used during lactation or alternatively, breastfeeding should be discontinued during treatment with tramadol

Fertility

South African recommendations

• The use of tramadol/ dexketoprofen may impair female fertility and is not recommended in women attempting to conceive

South African recommendations

• Mild (CrCl 60-89ml/min): Caution; dose adjustment recommended
  Max. dose: 2 tab/24hrs
  Moderate to severe (CrCl≤59ml/min): Contraindicated

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Max. dose: 2 tab/24hrs
  Patients should be closely monitored
• Severe: Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  Recommended initial dose: 1 tab, daily; Additional doses can be taken as needed with the min. dose interval of 8hrs; Max. dose: 2 tab (150mg tramadol hydrochloride/ 50mg dexketoprofen)/24hrs
  The dosage may be increased to a maximum of 3 daily film-coated tablets as for adults <65 years of age only after good general tolerance has been ascertained
  Limited data are available in patients over 75 years, therefore tramadol hydrochloride/ dexketoprofen should be used with caution in these patients

Dexketoprofen

Blood And Lymphatic System Disorders

Very rare

• Neutropenia
• Thrombocytopenia

Immune System Disorders

Rare

• Laryngeal oedema

Very rare

• Anaphylactic reaction, including anaphylactic shock
• Hypersensitivity (e.g. dyspnoea, bronchospasm, wheezing, angioedema)

Metabolism And Nutrition Disorders

Rare

• Decreased appetite

Psychiatric Disorders

Uncommon

• Insomnia
• Anxiety

Nervous System Disorders

Uncommon

• Headache
• Dizziness
• Somnolence

Rare

• Paraesthesia
• Syncope

Eye Disorders

Very rare

• Blurred vision

Ear And Labyrinth Disorders

Uncommon

• Vertigo

Very rare

• Tinnitus

Cardiac Disorders

Uncommon

• Palpitations

Very rare

• Tachycardia

Vascular Disorders

Uncommon

• Flushing

Very rare

• Hypotension

Respiratory, Thoracic And Mediastinal Disorders

Rare

• Bradypnoea

Very rare

• Bronchospasm
• Dyspnoea

Gastrointestinal Disorders

Common

• Nausea and/or vomiting
• Abdominal pain
• Diarrhoea
• Dyspepsia

Uncommon

• Gastritis
• Constipation
• Dry mouth
• Flatulence
• Gastrointestinal tract irritation

Rare

• Peptic ulcer
• Peptic ulcer haemorrhage
• Peptic ulcer perforation

Very rare

• Pancreatitis

Hepatobiliary Disorders

Rare

• Hepatitis
• Hepatocellular injury
• Increased hepatic enzyme, including abnormal liver function tests and increased gamma-glutamyl transferase

Skin And Subcutaneous Tissue Disorders

Uncommon

• Rash

Rare

• Urticaria
• Acne
• Hyperhidrosis

Very rare

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (Lyell’s syndrome)
• Facial oedema
• Photosensitivity reaction
• Pruritus

Musculoskeletal And Connective Tissue Disorders

Rare

• Back pain

Renal And Urinary Disorders

Rare

• Acute renal failure
• Polyuria

Very rare

• Nephritis
• Nephrotic syndrome

Reproductive System And Breast Disorders

Rare

• Menstrual disorder
• Prostatic disorder

General Disorders And Administration Site Conditions

Uncommon

• Fatigue
• Pain
• Asthenia
• Chills
• Malaise

Rare

• Peripheral oedema

Investigations

Rare

• Increased blood pressure

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Tramadol

Immune System Disorders

Rare

• Anaphylactic reaction, including anaphylactic shock
• Hypersensitivity (e.g. dyspnoea, bronchospasm, wheezing, angioedema)

Metabolism And Nutrition Disorders

Rare

• Appetite disorder

Not known

• Hypoglycaemia

Psychiatric Disorders

Rare

• Anxiety
• Cognitive disorder
• Confusional state
• Dependence
• Hallucination
• Altered mood
• Nightmare
• Sleep disorder

Nervous System Disorders

Very common

• Dizziness

Common

• Headache
• Somnolence

Rare

• Coordination abnormal
• Epilepsy
• Muscle contractions involuntary
• Paraesthesia
• Sensory disturbance
• Syncope
• Tremor

Not known

• Speech disorder

Eye Disorders

Rare

• Blurred vision
• Miosis

Not known

• Mydriasis

Cardiac Disorders

Uncommon

• Palpitations
• Tachycardia

Rare

• Bradycardia

Vascular Disorders

Uncommon

• Circulatory collapse
• Orthostatic hypotension

Respiratory, Thoracic And Mediastinal Disorders

Uncommon

• Respiratory depression

Rare

• Dyspnoea

Gastrointestinal Disorders

Very common

• Nausea

Common

• Constipation
• Dry mouth
• Vomiting

Uncommon

• Abdominal discomfort
• Abdominal distension
• Diarrhoea
• Retching

Hepatobiliary Disorders

Very rare

• Increased hepatic enzyme, including abnormal liver function tests and increased gamma-glutamyl transferase

Skin And Subcutaneous Tissue Disorders

Common

• Hyperhidrosis

Uncommon

• Pruritus
• Rash
• Urticaria

Musculoskeletal And Connective Tissue Disorders

Rare

• Weakness

Renal And Urinary Disorders

Rare

• Dysuria
• Micturition disorder
• Urinary retention

General Disorders And Administration Site Conditions

Common

• Fatigue

Rare/very rare

• Drug withdrawal syndrome
  - Agitation
  - Anxiety
  - Nervousness
  - Insomnia
  - Hyperkinesia
  - Tremor
  - Gastrointestinal symptoms
  Rare:
  - Panic attacks
  - Severe anxiety
  - Hallucinations
  - Paraesthesias
  - Tinnitus
  - Unusual CNS symptoms e.g. confusion, delusions, depersonalisation, derealisation, paranoia

Investigations

Rare

• Increased blood pressure

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Tramadol Hydrochloride/ Dexketoprofen

Blood And Lymphatic System Disorders

Uncommon

• Thrombocytosis

Immune System Disorders

Uncommon

• Laryngeal oedema

Metabolism And Nutrition Disorders

Uncommon

• Hypokalaemia

Psychiatric Disorders

Uncommon

• Psychotic disorder

Nervous System Disorders

Common

• Dizziness

Uncommon

• Headache
• Somnolence

Eye Disorders

Uncommon

• Periorbital oedema

Ear And Labyrinth Disorders

Uncommon

• Vertigo

Cardiac Disorders

Uncommon

• Tachycardia

Vascular Disorders

Uncommon

• Hypertensive crisis
• Hypotension

Gastrointestinal Disorders

Common

• Nausea and/or vomiting

Uncommon

• Abdominal distention
• Constipation
• Dispepsia

Hepatobiliary Disorders

Uncommon

• Increased hepatic enzyme, including abnormal liver function tests and increased gamma-glutamyl transferase

Skin And Subcutaneous Tissue Disorders

Uncommon

• Face oedema
• Urticaria
• Hyperhidrosis

Renal And Urinary Disorders

Uncommon

• Haematuria

General Disorders And Administration Site Conditions

Uncommon

• Asthenia
• Chills
• Discomfort
• Feeling abnormal

Investigations

Uncommon

• Increased blood pressure
• Increased blood alkaline phosphatase
• Increased blood lactate dehydrogenase

Dexketoprofen

• Other nonsteroidal anti-inflammatory drugs (NSAIDs)
• Cyclooxygenase-2 selective inhibitors
• High doses of salicylates (≥3 g/day)
• Anticoagulants
• Warfarin
• Heparins
• Corticosteroids
• Lithium
• Methotrexate
• Hydantoins
• Sulphonamides
• Diuretics
• ACE inhibitors
• Antibacterial aminoglycosides
• Angiotensin II receptor antagonists
• Pentoxifylline
• Zidovudine
• Sulfonylureas
• Beta-blockers
• Ciclosporin
• Tacrolimus
• Thrombolytics
• Antiplatelet medicines
• Selective serotonin reuptake inhibitors (SSRIs)
• Probenecid
• Cardiac glycosides
• Digoxin
• Mifepristone
• Quinolone antibiotics
• Tenofovir
• Deferasirox
• Pemetrexed

Tramadol

• Monoamine oxidase (MAO) inhibitors
• Coumarin derivatives
• Warfarin
• Mixed opioid receptor agonist/antagonist medicines
• Buprenorphine
• Nalbuphine
• Pentazocine
• Serotonergic medicines
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants
• Antipsychotics and other seizure threshold-lowering medicines
• Bupropion
• Mirtazapine
• Tetrahydrocannabinol
• Sedative medicines
• Benzodiazepines
• Other centrally depressant medicines
• Carbamazepine
• Ondansetron
• CYP3A4 inhibitors
• Ketoconazole
• Erythromycin

Other interactions (tramadol)

• Alcohol

Specific cases may require

• Renal function
• Hepatic impairment
• Blood pressure
• Cardiac function
• Respiratory function
• Laboratory levels (for warfarin and heparins, when coadministered)
• Lithium levels (when coadministered)
• Full blood count (when coadministered with methotrexate)

Additional observations

• Digestive disturbances, especially gastrointestinal bleeding
• Bleeding time (when coadministered with pentoxifylline)
• Skin reactions
• Mental status
  - In patients with a tendency to drug abuse or dependence, treatment with tramadol/ dexketoprofen should only be carried out for short periods under strict medical supervision

Dexketoprofen

Dexketoprofen is the tromethamine salt of S-(+)-2-(3-benzoylphenyl)propionic acid, an analgesic, anti-inflammatory and antipyretic drug, which belongs to the nonsteroidal anti-inflammatory group of drugs (M01AE). The mechanism of action of nonsteroidal anti-inflammatory drugs is related to the reduction of prostaglandin synthesis by the inhibition of cyclooxygenase pathway. There is inhibition of the transformation of arachidonic acid into cyclic endoperoxides, PGG2 and PGH2, which produce prostaglandins PGE1, PGE2, PGF2α and PGD2 and also prostacyclin PGI2 and thromboxanes (TxA2 and TxB2). The inhibition of the synthesis of prostaglandins could affect other inflammation mediators such as kinins, causing an indirect action which would be additional to the direct action. Dexketoprofen has been demonstrated to be an inhibitor for COX-1 and COX-2 activities in experimental animals and humans.

Tramadol Hydrochloride

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. It is a non-selective, partial agonist of μ-, δ- and κ-opioid receptors with a higher affinity for μ-receptors. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the Odemethylated metabolite M1 to µ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in µ-opioid binding. Tramadol-induced analgesia is only partially antagonised by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro. These mechanisms may contribute independently to the overall analgesic profile of tramadol. Tramadol has an antitussive action. The potency of tramadol is reported to be 1/10 (one tenth) to 1/6 (one sixth) that of morphine.