Pain is among the most prevalent and debilitating symptoms experienced by patients with advanced cancer. The current approach to treatment follows the World Health Organization (WHO)’s “analgesic ladder,” a stepwise strategy for using analgesic medications. This method progresses from nonopioids (Step 1, such as aspirin and nonsteroidal anti-inflammatory drugs) to weak opioids combined with nonopioids (Step 2, e.g., codeine), and finally to strong opioids paired with nonopioids (Step 3, e.g., morphine). Tramadol, classified as a Step 2 analgesic in the WHO guidelines for cancer pain management, is a centrally acting analgesic with a dual mechanism of action. It is a racemic compound that not only binds to opioid receptors but also modulates norepinephrine and serotonin activity at synapses.
Pharmacodynamics:
Tramadol and its primary metabolite (M1) are racemic mixtures. The parent compound, its enantiomers, and the enantiomers of the primary metabolite each exhibit varying affinities for opioid receptors and exert distinct effects on adrenergic and serotonergic metabolism at the synapse.
Engagement with opioid receptors:
Tramadol exhibits a low affinity for opioid receptors. Specifically, its affinity for μ-opioid receptors is thousands of times weaker than morphine and ten times weaker than codeine. The parent compound and its enantiomers do not interact with δ-opioid receptors and demonstrate only minimal interaction with κ-opioid receptors. Among its metabolites, the + enantiomer of the M1 metabolite shows the strongest affinity for μ-opioid receptors (Ki 153). This indicates that the analgesic effects of tramadol and its M1 metabolite are influenced by their respective plasma concentrations.
Engagement with the monoaminergic system:
Analgesia can be achieved both centrally and peripherally through interference with various neurotransmitter systems (nonopioid mechanisms). Pain modulation is influenced by descending pathways originating from brainstem regions like the locus coeruleus/subcoeruleus and the raphe complex, which are associated with noradrenaline (NA) and serotonin (5-HT), respectively. Tramadol impacts both the serotonin and noradrenergic systems, with its interaction with the monoaminergic system occurring at concentrations similar to those required for binding to μ-opioid receptors. Notably, tramadol shares a strong structural resemblance to the antidepressant venlafaxine, which also affects NA and 5-HT activity at the synapse.
Influence on the serotonergic pathway:
The parent compound, its enantiomers, the primary metabolite, and its enantiomers exhibit varying effects on serotonin (5-HT) activity at the synapse. Research on (+/-)-tramadol, (+)-tramadol, (-)-tramadol, and O-desmethyltramadol (M1 metabolite) using dorsal raphe nucleus brain slices has shown that racemic tramadol and its (+)-enantiomer significantly inhibit 5-HT reuptake and enhance stimulated 5-HT release. In contrast, the (-)-enantiomer of tramadol and its M1 metabolite are inactive in this regard.
Other Receptor Interactions:
Tramadol inhibits muscarinic type-3 receptor function, which is primarily involved in smooth muscle contraction and glandular secretion. However, tramadol does not affect arachidonic acid metabolism and does not interact with nonsteroidal anti-inflammatory drugs (NSAIDs).
CNS:
Adverse effects on the central nervous system (CNS) are common with tramadol and include symptoms such as drowsiness, dizziness, headache, and agitation. Notably, the headache associated with tramadol differs from those caused by other opioids and may be linked to serotonin blockade. Rare CNS side effects include mania and musical hallucinations. Seizures have been reported, even after a single therapeutic dose, but they are more likely to occur in individuals with risk factors such as a history of epilepsy, concurrent use of medications that lower the seizure threshold, or other seizure-prone conditions. Additionally, tramadol can cause or worsen cognitive impairment in individuals over the age of 75.
Gastrointestinal:
In clinical trials, the most common gastrointestinal side effects of tramadol were nausea (24%), vomiting (9%), and constipation (24%). However, postmarketing data indicates a lower incidence of nausea (4.2%) and vomiting (0.5%). Tramadol has a lesser impact on colonic transit time compared to morphine. Additionally, intravenous tramadol does not affect the bile duct sphincter.
Genitourinary:
Urinary retention or increased urinary frequency has been reported in up to 5% of patients receiving therapeutic doses of tramadol.
Respiratory:
Tramadol is not linked to respiratory depression and does not inhibit the hypoxic ventilatory response.
Other adverse effects:
Diaphoresis has been observed in up to 20% of patients treated with oral or parenteral tramadol. Fatigue and skin reactions have also been reported with tramadol use. Additionally, tramadol has been linked to the worsening of acute porphyria attacks. A small fraction (0.1%) of the administered dose is excreted into breast milk.
Comparison with morphine:
Table 2 compares the side effects of morphine and tramadol. Unlike morphine, tramadol has not been shown to cause myoclonus or hyperalgesia. While it is reported to cause less histamine release, pruritus can still occur (see Table 1). Tramadol is not linked to respiratory depression and does not suppress the hypoxic ventilatory response. It may also be less immunosuppressive than morphine. Additionally, tramadol has minimal cardiovascular side effects.
Withdrawal has been reported with long-term tramadol use, but due to its weak interaction with opioid receptors, it is considered a non-habit forming and non-dependence-producing analgesic. As a result, it is not classified as a controlled substance by the U.S. Food and Drug Administration. However, surveillance studies and case reports indicate that withdrawal symptoms can occur. In most instances, these symptoms resemble typical opioid withdrawal, but some cases have involved additional symptoms not usually seen in opioid withdrawal, such as hallucinations, paranoia, severe anxiety, panic attacks, confusion, and unusual sensory experiences like numbness and tingling in one or more limbs. These symptoms are more likely to occur after sudden discontinuation, particularly if the drug had been used for over a year. Patients should be informed about the possibility of such effects when stopping tramadol or when transitioning to another medication. To minimize withdrawal symptoms, the dosage should be gradually reduced.
Tramadol for cancer pain?:
Table 3 summarizes studies involving tramadol and cancer pain. Grond and colleagues compared the efficacy and safety of high doses of oral tramadol (≥ 300 mg per day) with low doses of oral morphine (≤ 60 mg per day). This non-blinded, non-randomized study included patients whose combination of a nonopioid analgesic and up to 250 mg per day of tramadol was insufficient. The average tramadol dosage was 428 ± 101 mg per day (ranging from 300 to 600 mg), while the average morphine dosage was 42 ± 13 mg per day (ranging from 10 to 60 mg). The mean pain intensity was similar between the two groups. Constipation, neuropsychological symptoms, and pruritus were significantly more frequent in the low-dose morphine group, while other symptoms occurred with similar frequencies in both groups.
In a study involving patients with moderate to severe cancer pain who had inadequate pain relief from nonopioid analgesics, Petzke and colleagues investigated slow-release tramadol for initial dosing and long-term treatment. Immediate-release tramadol was used for breakthrough pain, alongside oral Naprosyn 500 mg twice a day. Of the 146 patients, 90 (62%) completed the six-week trial. Both average and maximum pain intensity decreased from day one to day four. The percentage of patients experiencing good or complete pain relief increased from 43% at week one to 71% at week six. The maximum daily dosage of tramadol reached up to 650 mg, but 70% of patients required less than 400 mg per day by week six. The occurrence of some common opioid side effects, such as fatigue, dizziness, and constipation, decreased over the six weeks. However, the frequency of other side effects, like nausea, vomiting, and sweating, remained unchanged. Slow-release tramadol provided fast and effective pain relief for nearly two-thirds of patients during both the initial dosing phase and long-term treatment.
Tramadol for neuropathic pain?:
Table 4 summarizes studies on tramadol and neuropathic pain. Tramadol was found to be more effective than a placebo in managing pain in diabetic neuropathy and postherpetic neuralgia. In patients with polyneuropathy, Sindrup observed that tramadol was effective in treating allodynia. Harati reported that tramadol use in diabetic neuropathy was linked to improved quality of life. However, there is no available data on tramadol’s effectiveness for neuropathic pain in cancer patients.
Pharmacoeconomics:
The average wholesale price of Ultram (tramadol 50 mg) is $1.21 per tablet, while generic tramadol online costs $0.84. The price of Ultracet is $1.07. Table 5 compares the cost of tramadol with other Step 2 analgesics.
Schedule of administration:
The oral dosage of tramadol is one or two 50-mg tablets, taken up to four times daily, with a maximum of eight tablets per day. The tramadol/acetaminophen fixed combination is available in 37.5/325 mg tablets, with a recommended dosage of two tablets every four to six hours. The extended-release formulation of tramadol hydrochloride (tramadol ER), administered as 100 mg twice daily, is considered therapeutically equivalent to the immediate-release formulation of 50 mg taken four times daily. In cases of severe kidney impairment (creatinine clearance below 30 mL per minute) or liver dysfunction, a dosage reduction (about 50%) or an extended dosing interval should be considered.
Prostate Biopsies
Tramadol can be used to alleviate pain during prostate biopsies. A study showed that an oral combination of 75 mg of tramadol and 650 mg of acetaminophen, along with 1% lidocaine, effectively and safely managed pain during a transrectal ultrasound-guided prostate biopsy.
Pain is a common issue for cancer patients, affecting 60–90% of those with advanced-stage cancer. Bone pain is the most frequently experienced type of pain in cancer patients.