A common misconception: As tolerance develops to the analgesic effects of an opioid, the dose needed to relieve pain becomes closer and closer to the dose needed to fatally overdose.
First and foremost, let me explain the meaning of the term "Therapeutic Index": The margin of safety between the clinically adequate dose of a drug and the average lethal dose of said drug. In other words, the therapeutic index of any particular drug, is determined by the margin between the clinically effective dose to the lethal dose. For some drugs, barbiturates for instance; the therapeutic dose is extremely close to the potentially lethal dose, leaving a narrow margin of error, or narrow 'therapeutic index'.
In the case of opioids, there are many factors at play in determining the overall safety of the drugs. The only serious risk with opioids is the acute risk of toxicity. Aside from this, opioids cause no organic tissue damage to the organs or otherwise, even taken over years. The sole mechanism behind acute opioid toxicity is respiratory depression - via a reduction in brain responsiveness/sensitivity to increasing CO2 levels.
Respiratory depression is mediated via the mu-2 receptor subtype, whereas analgesia and euphoria is mediated via the mu-1 receptor type. Therefore, we can conclude that the rate at which tolerance develops (if even at all) may not be consistent between these two distinctly mediated effects.
We know however, that there is a progression of pharmacological tolerance to the analgesic (and euphoric) efficacy of opioid agonists. Additionally, we know that tolerance does develop to the effects of respiratory depression, as well as sedation/somnolence, nausea & vomiting. A marked degree of tolerance can be seen with respiratory depression after several days of regular use.
Tolerance continues to develop to the respiratory effects of the narcotic, just as tolerance continues to develop to the antinociceptive and euphorigenic properties; albeit at different rates.
Typically in both the therapeutic and the recreational setting, narcotic dose is periodically titrated upwards to compensate the progressive development of analgesic/euphoric tolerance. This is done succesfully. All the time.
Keeping in mind that in the context of chronic pain treatment, physicians typically do not exceed 25-50% increase rates - Patients and users of narcotics are known to require 10+fold the initial therapeutic dose, and safely maintain with regular high doses which may undoubtedly prove lethal to a non-tolerant individual. Upward titrations are made for years to decades, into the 4-digit range of oral, or even IV morphine, multiple times daily. All while showing no signs of intoxication, no nausea or vomiting, and no marked level of respiratory depression. We can conclude in these many instances (of competent non-clinical & clinical use) that the development of tolerance to the intended effects (euphoria, analgesia) progressed at a rate slower than that of the tolerance to respiratory depression, etc.
It is important however to keep in mind that limiting the development of subjective tolerance is crucial, as to consistently maintain an acceptable therapeutic margin and to avoid the emergence of adverse events (resp. depression, somnolence).
In many cases of negligence on either prescribing physician, or the patient/user, there have been incidents which may highlight this inconsistency in tolerance development to these varying functions.
This exemplifies the need to remain consistent and prudent in dosing, adjusting periodically by no greater than 25-50%, with smaller increments of increase as dose move higher upwards (15-25%), or better yet, the utilization of opioid rotation; as switching to an alternate opioid with an incomplete degree of cross tolerance will allow for lower relative dosing. It is also important to make use of adjuvant analgesic agents as well as potentiating agents; atypical analgesics such as NRI-SNRI type agents, as well as NMDA antagonists such as dextromethorphan (DXM) or low dose ketamine - these allow for lower total doses of opioid to be used. Additionally, NMDA antagonism is believed to play a role in slowing the development of analgesic tolerence to opioids.
Certain narcotics show additional modes of action; tramadol & tapentadol work as NRI's in addition to modest mu-agonism. Methadone and Levorphanol have additional activity as antagonists at NMDA receptors, and work particularly well in opioid rotation protocols, while sharing the least amount of cross tolerance with morphine and other typical narcotics.
Despite the lunacy in suggesting that chronic opioid use marked by increasing clinical tolerance is a sure path to an impending overdose, a level of caution is always advised. We do know that tolerance does in fact develop to opioid induced toxicity (respiratory depression), rather than simply stand still marking an impending overdose, as often suggested by drug counselors and popular media.
We can conclude that the development of pharmacological tolerance to the beneficial effects versus the side effects tend to develop at different rates; therefore the goal in chronic use is to limit (as much as we practically can at least) the development of analgesic/euphoric tolerance, to a rate below that of toxic tolerance, as to allow a consistent and favorable therapeutic index, with a comfortable margin for error.
In the event that adverse effects do limit an upward increase in dose, conversion to an alternate opioid, or implementation of a full opioid rotation is essential.