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Tramadol hydrochloride was invented by the pharmaceutical company Gruenenthal GmbH, located in Stollberg, Germany, in late 1970s. It was launched in Germany in 1977 as an oral immediate-release formulation under the brand name Tramal. Since then, various formulations containing tramadol hydrochloride have been launched in more than 100 countries worldwide.

Grunenthal, founded in 1946 is an independent, family-owned, research-based pharmaceutical company. It was the first company to engage in industrial production of penicillin and to commercialise it. Today analgesics are their main competence. Beside this Grunenthal is active in the marketing of oral contraceptives and the treatment of respiratory tract diseases 3.

In the U.S., immediate-release oral tramadol, is marketed under the brand name Ultram by Ortho-McNeil, a division of Johnson & Johnson. Ortho-McNeil's primary concentration is on the manufacturing and testing of drugs used to treat pain, acid reflux and infectious diseases.

• management of moderate to moderately severe pain in adults
  

Tramadol is used to treat the following types of pain:

• dental pain
• osteoarthritis pain 4, 6
• neuropathic pain 17
• posttraumatic pain 11
• postoperative pain 19
• acute musculosketetal pain
• labour pain, obstetrical analgesia 18, 33
• renal colic pain 22
• diabetic neuropathy pain 5, 20
• postherpetic neuralgia 13
• low back pain 7
• chronic pancreatitis pain 25
• rheumatoid arthritis pain

• premature ejaculation 16
• diabetic neuropathy 5, 20
• postherpetic neuralgia 13, 21
• fibromyalgia 8, 15
• restless legs syndrome 30
• acute myocardial infarct 24
• opiate withdrawal management 27
• migraine headache 31

Tramadol for osteoarthritis
Tramadol may be a useful alternative in patients with osteoarthritis who have not responded to first-line treatment with acetaminophen and in whom nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated, ineffective, or poorly tolerated 6. It appears to be relatively well tolerated for an opioid compound.

Tramadol for postherpetic neuralgia
Tramadol appears to be an interesting therapeutic alternative for pain relief in postherpetic neuralgia, particularly in patients who are not depressed. Tramadol may be the drug of first choice in patients with obvious cardiovascular disease in whom antidepressants are contraindicated, and similarly in patients in whom an antidepressant effect is not required 13.

Tramadol for restless legs syndrome
Compared with other treatments for RLS, tramadol seems to be superior in some cases, possibly because of its unique pharmacodynamic profile. In clinical study 12 patients with RLS (some of them treatment resistant or prone to side effects of previous medications) were treated with 50 to 150 mg of tramadol per day. The follow-up lasted from 15 to 24 months. 10 patients reported clear amelioration and 1 reported slight amelioration of their symptoms, while 1 reported no effect. Tramadol was described to be the most effective treatment and free of side effects when compared with several other treatments 30.

Tramadol for fibromyalgia
Tramadol is effective in patients with mild to moderately severe pain. It should be titrated to avoid nausea and dizziness associated with high initial doses. A tramadol/acetaminophen (Ultracet) (37.5/325 mg) combination has been shown to be effective for fibromyalgia pain without any serious adverse effects 8.

• Advantages:
• generally well tolerated
• proven efficacy in a broad range of painful conditions
• respiratory depressionis less common and less pronounced than with other opioids 10
• lesser constipation effect than with other opioids 26
• withdrawal not considered to be as severe as that produced by other opioids
• low abuse and dependence potential 29, 28, 34
• more effective than NSAIDs for controlling post operative pain
• antidepressant-like (mood improving) activity 12
• local anesthetic activity 14
• low interaction potential
• devoid of immunosuppressive activity
• reasonably priced - available generic formulation
• Disadvantages:
• risk of seizures 23
• risk of abuse, dependence and tolerance
• relatively high incidence of nausea and vomiting
• withdrawal symptoms following abrupt discontinuation 2
• short half-life necessitates dosing of immediate-release formulation every 4 to 6 hours

Tramadol has dual mechanism of action. The results of clinical studies suggest that tramadol-induced antinociception is mediated by opioid (µ, mu) and non-opioid (inhibition of re-uptake of norepinephrine and serotonin) mechanisms 9. There is evidence that, in tramadol, both mechanisms act synergistically with respect to analgesia.

Its major metabolite O-desmethyl tramadol (M1) has a weak affinity at µ-opioid receptors as an agonist. The monoaminergic activity comes through the two stereoisomers of tramadol itself, which act synergistically on serotonergic and noradrenergic mechanisms of pain transmission. More specifically, tramadol enhances spinal pain inhibitory pathways by inhibiting neuronal re-uptake of serotonin (5-HT) and noradrenaline (NA), and stimulating 5-HT release.4,5 This added monoaminergic component possibly allows tramadol’s efficacy to stretch over a wider range of painful pathologies than other opioids.

Opioid activity: Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to m-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.

Non-opioid activity: Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin. These mechanisms may contribute independently to the overall analgesic profile of tramadol.

Tramadol has a dose-dependent efficacy that lies between that of codeine and morphine, with a parenteral potency comparable to that of pethidine, i.e. about 10-20% of the gold standard morphine 33, 35.

Tramadol half-life is 6.3 h and 7.4 h of the metabolite. It may take from 31 to 38 hours to clear out of the system.

Tramadol and its metabolites are mainly excreted via the kidneys.

The onset of analgesia begins approximately within one hour after administration.

Tramadol increases the risk of CNS and respiratory depression when used with alcohol.

Withdrawal symptoms may occur if tramadol is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely hallucinations. Other symptoms that have been seen less frequently with Ultram discontinuation include panic attacks, severe anxiety, and paresthesias. Withdrawal symptoms may be avoided by tapering tramadol at the time of discontinuation.

Abrupt cessation from tramadol has been associated with two types of withdrawal syndromes 2:

• Opioid-like withdrawal. One is typical of opioid drugs with flu-like symptoms, restlessness and drug craving. This type of withdrawal syndrome is encountered in about 90% of cases of withdrawal from tramadol.
• Atypical withdrawal. Another withdrawal syndrome (encountered in about 10% of cases of tramadol withdrawal) is atypical of opioids and is associated with hallucinations, paranoia, extreme anxiety, panic attacks, confusion, and numbness and tingling in the extremities.

• Tramadol (Ultram) versus Other Medications
• Tramadol without a prescription - how it differs from NSAIDs and opioids, when it is effective.

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Published: March 31, 2008
Last updated: January 07, 2010