Tramadol belongs to a group of drugs called Analgesics. The word 'Analgesic' has Greek origins: “an-” (meaning “without”) and “algos” (which means “pain”), that's why they are also often called 'painkillers'.

Pain can be relieved by acting either locally or centrally, so all the analgesics are divided into 2 broad categories:

  • peripherally-acting (affecting peripheral nervous system)
  • centrally acting (affecting central nervous system)

Tramadol belongs to the second group from the list, centrally acting analgesics.

Classifying Analgesics by the mechanism of action, Tramadol is included into the group called 'Opioids': Opioids work by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract.

Opioids can be further classified by their's origins into:

  • Natural: Contained in the resin of opium poppy
  • Semi-Natural: Produced from the natural opioids
  • Fully Synthetic: Synthesized in-vitro
  • Endogenous: Produced naturally in the body

According to this classification, Tramadol is not an opioid chemically, however, acts as an agonist by binding to μ-opioid receptors. This is the key to understanding mechanisms of action of Tramadol and is considered in details below.

What is a μ-opioid receptor?

In 1973 an important breakthrough in the research of opioids occurred. Solomon Snyder and Candace Pert at Johns Hopkins School of Medicine in Baltimore, Maryland, discovered receptors on brain cells to which opium would bind. Receptors are molecular groups within the cells that have a special affinity for toxins. These receptors have come to be called opioid receptors.

Snyder and Pert found two locations in the central nervous system where opioid receptors are most common:

  • One is in the spinal column. It is here that pain is first detected.
  • The second in the medial thalamus of the brain, where chronic pain is often concentrated.

The opioid receptors are subdivided into 4 types:

Receptor Subtypes Function
delta (δ) OP1 δ1, δ2
  • analgesia
  • antidepressant effects
  • physical dependence
kappa (κ) OP2 κ1, κ2, κ3
  • spinal analgesia
  • sedation
  • miosis
  • inhibition of ADH release
  • dysphoria
mu (μ) OP3 μ1, μ2, μ3
  • supraspinal analgesia
  • physical dependence
  • respiratory depression
  • miosis
  • euphoria
  • reduced GI motility
  • physical dependence
Nociceptin receptor OP4 ORL1
  • anxiety
  • depression
  • appetite
  • development of tolerance to μ agonists

Locations of the opioid receptors in the CNS are summarized in the picture below:

Location of Opioid Receptors

What is agonist?

An agonist is a chemical that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance.

An agonist produces an action. An antagonist blocks an action of an agonist.

Receptors can be activated or inactivated by either endogenous (such as hormones and neurotransmitters) or exogenous (such as drugs) agonists and antagonists, resulting in stimulating or inhibiting a biological response.

How does it work?

Solomon and Pert hypothesized that opium locks into opioid receptors on a cell. It then slows the rate at which that cell can transmit a "pain" message. These two actions may also be responsible for the sense of euphoria (bliss, happiness) that accompanies opium use.

Later, this hypothesis appeared to be true. The analgesic effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance. The side effects of opioids include sedation, respiratory depression, and constipation. Physical dependence can develop with ongoing administration of opioids, leading to a withdrawal syndrome with abrupt discontinuation.

The analgesic action of Tramadol has yet to be fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its mild agonism of the μ-opioid receptor (besides being μ-opioid agonist, Tramadol acts as serotonin releasing agent, and norepinephrine reuptake inhibitor).

When taking Tramadol, you should be extremely aware that it's an opioid and can result in addiction and withdrawal syndrome.