Baseline (Prevention)

Opioids include synthetic and semi-synthetic drugs like fentanyl, oxycodone, and methadone. Opiates refer to natural alkaloids from opium: morphine, codeine, and thebaine.
To prevent tolerance:

• Rotate compounds (e.g., morphine ↔ hydromorphone)

• Use the lowest effective dose

• Introduce NMDA antagonists like low-dose ketamine or memantine intermittently

Active Tachyphylaxis

Once tachyphylaxis is active:

• Rotate to a lower cross-tolerance compound (e.g., switch from oxycodone to tapentadol or levorphanol)

• Add NMDA antagonists daily for a week

• Consider low-dose ibogaine or mitragynine (kratom alkaloid) cautiously for receptor reset

• Microdosed naltrexone (0.5–1 mg) may paradoxically upregulate MOR sensitivity

Withdrawal Transition

• Initiate a taper or switch to a partial agonist (buprenorphine) or weak full agonist (tramadol)

• Introduce clonidine or lofexidine to manage adrenergic rebound

• Use gabapentin, L-theanine, and magnesium to reduce somatic hyperexcitability

Neurorestoration Phase

• Support the endogenous endorphin system with:

  • Cold exposure

  • Aerobic activity

  • Adaptogens (e.g., rhodiola)

• Supplement with DLPA (DL-phenylalanine) to inhibit enkephalinase

• Use N-acetylcysteine to support glutamate homeostasis

• Explore low-dose naltrexone cycling (3–5 mg/day) for opioid receptor density recalibration

Maintenance / Reinforcement

• Avoid recreational opioid reuse

• For pain management, rotate to kappa agonists or biased ligands (e.g., cebranopadol, when available)

• Reinforce dopaminergic and serotonergic tone through non-opioid hedonic pathways:

  • Oxytocin, music, social bonding

• Keep NMDA antagonists on hand (PRN)