Reversing Opiate Tolerance With Ketamine

The most reliable way to reduce opiate tolerance is to take a break from opiates. This is not always feasible, however. Chronic pain patients may be unable to "just stop" using opiates, for example.

What is Tolerance?

Addictive drugs can cause a cycle of tolerance, dependence, withdrawal and reinstatement. There is considerable folklore about the development of extreme tolerance to opiates. For example, some users have claimed to be tolerant to 20mg of fentanyl, which is 10-fold higher than the lethal dose of fentanyl in a drug naive individual.

Tolerance refers to needing an escalating dose of a substance in order to achieve the same effect. When a drug is introduced into the body, a series of adaptions take place in the brain to limit the effects of the drug. Tolerance helps return the brain to homeostasis. This phenomena is called tachyphylaxis.

At the level of receptors and gene trascription, tachyphylaxis can be caused by receptor downregulation, a decrease in receptor density or sensitivity, or decreased receptor gene transcription. Other mechanisms include decreased rate of receptor insertion into the plasma membrane.

Ketamine Reduces Opiate Tolerance

Recent publications support the idea that ketamine and other NMDA receptor antagonists reverse tolerance to opiates, in addition to other drugs.

NMDA antagonists are molecules that “block” this particular glutamate receptor, preventing a signal from being transduced from outside the cell into the cytoplasm.

Most of these studies were conducted in animal models. However, human data using clinically available NMDA receptor blockers supports this hypothesis. Here's a list of common NMDA antagonists:

  • Ketamine - anesthetic, now re-purposed for the treatment of depression

  • Dextromethorphan (DXM) - available OTC as a cough suppressant

  • Memantine - Alzheimer's drug and nootropic

  • Magnesium - essentail dietary mineral

  • Atomoxetine - norepinephrine reuptake inhibitor used for the treatment of ADHD

  • Phencyclidine (PCP)

Ketamine reduces tolerance to opiates by antagonizing the NMDA receptor, like the drugs listed above. It was recently reported that changes in brain electrical activity during rapid opiate detoxification are reversed by ketamine. Animal studies also show that ketamine markedly suppresses opiate withdrawal symptoms.

One study in humans reported that sub-anesthetic ketamine infusions (comparable to the dose of ketamine given to depressed patients) was an effective adjuvant in the correction of acute precipitated opiate withdrawal. However, the difference between the ketamine and control arms of the study were not significantly different on follow-up in terms of outcomes like average time opiate-free.

Ketamine Dosage For Reducing Tolerance

Only sub-anesthetic doses of ketamine are needed for opiate tolerance reduction. Ketamine will reverse tolerance at the same dose that ketamine acts as an antidepressant (0.5 mg/kg or 35 mg for a 70kg individual).

Other Strategies To Reduce Opiate Tolerance

  • Interestingly, the cancer drug Imatinib reduces opiate tolerance. Chronic morphine treatment induces the modification of a signaling protein called PDGFR-beta. This modification is reversed by Imatinib. PDGFR-beta is a neuropeptide that modulates mu-opioid receptor function.

  • Microglia are a type of immune cell in the brain that support neurons. It is now recognized that microglial cells play a role in opiate tolerance by releasing chemokines and other inflammatory molecules. There's some evidence that drugs that inhibit microglial activation like the antibiotic minocycline attenuate pain sensitivity and reduce opiate tolerance.

  • Low-dose naltrexone and naloxone have a role in mitigating opiate tolerance. These pure opiate receptor blockers should probably not be used at the same time as opiates (unless directed by your physician).

  • Chronic pain patients may lower their opiate tolerance by cycling between different classes of analgesic medicine. For example, benzodiazepines like Xanax, anticonvulsants like Gabapentin, and anesthetics like Ketamine have been used successfully for pain management. A patient could therefore temporarily switch from an opiate to an anticonvulsant like Gabapentin to lower opiate tolerance.