Injectable opiates & Tramadol
Injectable opiates, such as morphine, heroin, and fentanyl, exert their effects primarily through activation of the μ-opioid receptor (MOR), a G-protein-coupled receptor (GPCR) located throughout the central and peripheral nervous systems. Upon binding to MOR, these substances initiate a cascade of intracellular events that lead to analgesia, euphoria, and respiratory depression.
Activation of MOR inhibits adenylate cyclase activity, reducing cyclic adenosine monophosphate (cAMP) levels. This inhibition leads to decreased activity of protein kinase A (PKA), resulting in reduced phosphorylation of various downstream targets. Concurrently, MOR activation opens G-protein-gated inwardly rectifying potassium (GIRK) channels, causing an efflux of K⁺ ions and hyperpolarization of the neuron, making it less excitable. Additionally, MOR activation inhibits voltage-gated calcium channels, reducing Ca²⁺ influx and subsequent neurotransmitter release.
These combined effects diminish neuronal excitability and neurotransmission, particularly in pain pathways, leading to the characteristic analgesic effects of opiates. However, the same mechanisms also underlie adverse effects such as respiratory depression and constipation.
Tramadol is a centrally acting analgesic with a dual mechanism of action. It is a racemic mixture, with each enantiomer contributing differently to its pharmacological profile. The (+)-enantiomer is a weak agonist of the μ-opioid receptor, while the (−)-enantiomer inhibits norepinephrine reuptake. Both enantiomers also inhibit serotonin reuptake, leading to increased levels of these neurotransmitters in the synaptic cleft.
Upon administration, tramadol is metabolized in the liver by the cytochrome P450 enzyme CYP2D6 to O-desmethyltramadol (M1), which has a significantly higher affinity for MOR than the parent compound. This metabolite is primarily responsible for tramadol's opioid-like effects.
The inhibition of serotonin and norepinephrine reuptake enhances descending inhibitory pain pathways in the spinal cord, contributing to analgesia. However, increased serotonergic activity also raises the risk of serotonin syndrome, especially when combined with other serotonergic agents.
Combining injectable opiates with tramadol significantly increases the risk of adverse outcomes. Both substances depress the central nervous system (CNS) and respiratory function through MOR activation. When used together, their effects on respiratory centers can be compounded, leading to profound respiratory depression, hypoxia, and potentially fatal outcomes.
Besides, tramadol lowers the seizure threshold, particularly at high doses or when mixed with other CNS depressants. Add opioids, and the brain's excitability balance shifts—risk of tonic-clonic seizures goes up.
At last, tramadol is often underestimated because it’s perceived as “weaker.” Users may think it’s a “safe mix” with heroin or morphine—not realizing it can compound sedation and CNS depression.
Clinical studies and pharmacovigilance data have documented the dangers of combining tramadol with other opioids. Research indicates that the combination does not provide superior positive effects compared to either agent alone but does increase the incidence of adverse effects.
All things considered, we recommend avoiding this combination.
Last edited by a moderator: