**5. Biologic characteristics**

Tramadol is used as the first-line treatment in musculoskeletal pains [15,54-57] and as an alternative treatment in osteoarthritis (OA) patients in whom NSAIDs are contraindicated or those with resistant pain to oral analgesics [58].

Tramadol analgesic effects are due to the inhibition of norepinephrine and serotonin reuptake as well as agonism of mu receptors which cause blockage of the pain impulses in the spinal cord [7,56,59]. Direct administration of tramadol on the sciatic nerve can reduce the amplitude and speed of spinal somatosensory evoked potential in the rats emphasizing the analgesic effects of tramadol on the peripheral nerves [60].

In tramadol-induced anesthesia, the patient become conscious rapidly, has amnesia during the surgery, and experiences few side effects [61]. Controlled release of tramadol through polyhydroxybutyrate (PHB) microspheres is also available which induces longer anesthesia after epidural use in comparison with tramadol alone [62].

According to a study performed on the rats, tramadol reinforces the immune system by increasing phagocytosis. Use of tramadol is therefore favored as an analgesic in immunecompromised patients [63].
