DrugBuyers.Com: Ending Tolerance

Below is some pasted info on tolerance, some of it about other mechanisms outside the opioidergic system that may contribute to tolerance, although opioid receptor downregulation will always be the main factor in tolerance.

the second talks about DAMGO which isnt availible. the third talks about proglumide and tolerance, which has limited use, however proglumide can be obtianed. but at this point drug holidays are probably still the best for tolerance and of course one shouldn't try to reduce their tolerance with other drugs without consulting a qualified doctor.

lets all hope that these new findings with tolerance become practical and new medications or meds to argument with opioids come out soon.

The roles of pain facilitatory systems in opioid tolerance
by
Hsu MM, Wong CS Department of Anesthesiology,
Tri-Service General Hospital &
National Defense Medical Center,
Taipei, Taiwan, R.O.C.
Acta Anaesthesiol Sin 2000 Sep; 38(3):155-66

ABSTRACT
Opioids are powerful analgesic agents and have been widely used in clinical pain management for decades. Nevertheless, both acute and chronic opioids administration may produce tolerance, as indicated by a lowered responsiveness to the drugs at a later time. Koob and Bloom described two possible mechanisms of drug tolerance: a within-system and a between-systems adaptation. Opioid receptors uncoupling from G-proteins and receptor down-regulation, in particular the receptor's high affinity sites, are well-known mechanisms (the within-system) of opioid tolerance. A series of recent studies have proposed that a between-systems, particularly the pain facilitatory systems (opiate-activated opponent systems), may also involve in the development of opioid tolerance. Several lines of evidence suggest that N-methyl-D-asparate (NMDA) receptors activation and the subsequent nitric oxide (NO) production probably play a between-systems mechanism of opioid tolerance. Recently, our and others' studies also found that cyclooxygenase (COX) inhibitors could attenuate the opioid tolerance without enhancing morphine's antinociceptive effect. Taking all these findings together, the pain facilitatory systems included the NMDA-receptors, NO, and COX systems may also play important roles in opioid tolerance. In summary, except the opioid receptor uncoupling and opioid receptor down-regulation, chronic morphine treatment may also activate pain facilitatory systems (NMDA receptor activation, NO production, and COX ac-tivation) during opioid tolerance development. It implies that some complicated interactions may happen among the opioid receptor, NMDA-receptor, NO, and COX systems and are worth further investigations.

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Reducing Tolerance To Morphine
Could Aid Pain Therapy
Morphine is one of the most commonly used drugs in the treatment of severe and chronic pain. A major complication with its use over the long term is that patients develop tolerance to it, as well as becoming addicted.
A way of reducing tolerance would be of great benefit, because it would allow doctors to use lower doses over longer periods and still control pain effectively.

A study published in this week's issue of Cell provides just that, by showing that giving a small level of a different drug at the same time as morphine can reduce the development of tolerance.

As well as highlighting an exciting new way in which morphine treatment could be improved, this study also gives important new insights into the overall mechanisms that lead to tolerance, and underlines a change in thinking that has been developing over the past few years.

Morphine acts by binding a receptor (the mu opioid receptor) on the surface of nerve cells and signaling from it. When this receptor binds to its normal signaling molecule, it is activated and then becomes desensitized.

The receptor then moves into the cell by a process called endocytosis. Once in the cell, it can then be reactivated and transferred back to the cell surface, ready to bind to a new signaling molecule and signal again.

Morphine, however, is not able to cause the desensitization and recycling, so morphine-bound receptors stay on the cell surface. Until quite recently, most researchers assumed that endocytosis of the receptors contributed to tolerance, because it would reduce the number of receptors available on the cell surface for binding to morphine.

However, recent studies have led to an alternative view, in which endocytosis might in fact help to reduce tolerance by recycling the receptors so they can become active again.

Jennifer Whistler and colleagues, working at the University of California in San Francisco, published results relating to this in Neuron in December 2001, where they showed that endocytosis is associated with reduced tolerance in cultured cells. In the new study, Dr. Whistler's group develop their findings and, most importantly, take the therapeutically important step of showing that they also hold true in whole animals.

In the new paper, Drs. He, Fong, von Zastrow and Whistler looked at clustering of the receptors into groups. Morphine-bound receptors can still cluster, but they do not normally move into the cell interior.

However, the authors found that binding of a compound called DAMGO to a small number of receptors in a group can cause the whole group to be taken up.

This means that a small amount of DAMGO can drag other receptors that have bound morphine inside the cells, ready for recycling. This caused a reduction in tolerance in cell culture assays, and receptor endocytosis in the spinal cord.

Most significantly, however, the authors found that over a seven day morphine treatment, giving rats a small amount of DAMGO at the same time as the morphine eliminated the tolerance that would normally develop during that time.

On the seventh day, the morphine dose was essentially as effective as it was on the first.

The significance of these results is clear: if we can develop a drug that will act in the same way as DAMGO to promote receptor endocytosis, this could be used with morphine to reduce tolerance, and thus increase the effectiveness of treatment.

Up to now, many drug discovery programs have thrown away candidate drugs that cause desensitization and endocytosis of morphine receptors, because they were working on the assumption that they would increase tolerance.

These new results show that, in fact, the opposite seems to be true, and give new hope for pain relief.

(Reference: Endocytosis of the Mu Opioid Receptor Reduces Tolerance And a Cellular Hallmark of Opiate Withdrawal, A.K. Finn and J. Whistler, Neuron Vol. No. 32 [2001] 829-839.)

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Tolerance, Addiction and Effective Pain Management
some thoughts by K.Trout
A major problem faced by narcotics users and abusers is the well-known development of tolerance when an opiate is given repeatedly over a period of time. This is directly responsible for a number of the problems associated with narcotic use and abuse since increasing tolerance requires that steadily larger doses be used to achieve the same effects or degree of pain relief.
This also underlies much of the crime associated with street addiction as the cost of maintaining a habit also escalates along with the dosage, often leading addicts to turn to drug dealing, prostitution or criminal activities to enable them to afford their daily dose.

Many experienced junkies, especially if heroin users, address this problem by taking regular breaks from their drug of choice, allowing their tolerance to diminish and their effective dosage to also be decreased. Due to the unpredictable quality of unregulated black-market street drugs this can actually be potentially dangerous if they then acquire material of greater potency than they were expecting. (Junkies who relapse after recovery face a similar risk when they return to use.)

Some users employ materials like cimetidine (Tagamet) [R.A.H. 2000] to retard drug metabolism and thereby maximize their effectiveness. [An interesting but unrelated point worthy of further investigation is the report of Peterson et al. 1983 indicating that use of cimetidine one hour before and after administration of large amounts of cocaine to rodents prevented hepatic toxicity and liver damage. Pellinen et al. 1994 also reported a prevention of metabolism-related hepatotoxicity by use of Cytochrome P450 3A inhibitors.]

Other users recommend grapefruit juice (Anonymous 2000) to interfere with the metabolism of the opiates by the liver and small intestinal Cytochrome P450 enzyme CYP3A and thus attempt to maximize their per dose effects, blood concentration and duration. While this has been reported by many users to be effective at maximizing per dose results this does not affect the development of tolerance.

Presently many questions remain, as there is also been some conjecture made that administration of grapefruit juice might interfere with the conversion of codeine to morphine due to its lesser inhibition of some CYP subfamilies. This does not seem to be the case; Caraco et al. 1996 reported (in animals) that if codeine was coadministered with selective inhibitors of CYP3A4 this could result in increased morphine production and enhanced effects due to shunting into the CYP2D6 pathway (as CYP2D6 would NOT be affected).

It is worth noting that I can thus far locate NOTHING in the *scientific* literature specifically supporting the use of grapefruit juice to increase the general effectiveness of opiates or even that CYP3A is responsible for the metabolism of heroin. Although, it is certainly reasonable to assume that CYP3A is responsible for its metabolism since it is proven as such for other opioids such as codeine (Caraco et al. 1996) and fentanyl (Feierman & Lasker 1996)

Reports of successful application, circulating orally among users (Anonymous 2000 & 2001) and posted on web-based bulletin boards, are common enough that this should be investigated further.

It is important to keep in mind that grapefruit juice can also prove problematic due to the elevated levels of bioavailable drug, requiring a reduction of the dosage. Sometimes it can even be dangerous if certain other drugs are being used. The combination of grapefruit juice with some specific pharmaceuticals has produced many serious problems and even some deaths. (Ameer & Weintraub 1997; Dresser et al. 2000)

Another practice reportedly employed by some narcotic users is combining hydroxyzine with opiates to potentiate their effects. This is said to produce a rough doubling of intensity with the addition of unwanted side effects like a dry mouth. [Anonymous 2000] It appears to have no effect on the development of tolerance.

An interesting approach is the combination of opiates with the opiate antagonists naloxone or naltrexone in miniscule amounts. The combination of less than 0.001% of what would be a normal dose of the antagonist with an opiate allows a far greater response (at least 50%) to the opiate which in turn permits a much lower effective dose to be used. It is also said to prevent respiratory depression, tolerance and addiction. This approach has apparently been patented (Crain & Shen 1996) and is being commercially developed by Pain Therapeutics. [R.A.H. 2000; Crain & Shen 2000]

Another interesting comment was made by Karl Jansen (2001) concerning the administration of small oral doses of ketamine being found to be of use in chronic pain clinic for greatly reducing the development of tolerance (via blockade of NMDA receptors).

However, many people are unaware that both enhanced effectiveness of narcotic analgesics AND prevention or reversal of tolerance is readily achievable through the oral use of up to 200-250 mg of Proglumide [(DL)-4-Benzamido-N,N-dipropylglutaramic acid]. [See Ott 1999; Watkins et al. 1984]

The work of Watkins suggests there may be a therapeutic dosage window with diminished results above it but more detailed work to define this is apparently lacking.

Rather than simply augment the action of the opiates, proglumide actually interferes with the anti-opioid activity of the neuropeptide CCK.

The chronic administration of opiates, or spinal cord and other CNS injuries, elevates the level of Cholecystokinin (CCK) that is present. Such elevated levels exert an antagonistic effect on opioid activity resulting in significantly diminished analgesic effects. (Watkins et al. 1984; Xu et al. 1993 & 1994)

It is this rise in CCK levels that directly leads to the condition known as drug tolerance and the corresponding increase in its anti-opioid activity that requires the opiate user to use increasingly larger amounts to achieve the same effects.

This anti-opiate effect can be prevented or even reversed through the administration of CCK inhibitors such as proglumide. (Watkins et al. 1984)

Besides just interfering with the adverse action of CCK on opiate activity, proglumide is also known to augment the analgesic effect of opiates. Often this can provide a higher quality of analgesia for those patients who suffer from an incomplete response to pain medications.

Watkins & coworkers reported that proglumide reversed morphine tolerance and also 1) hastened the onset of analgesia, 2) increased the peak levels, and 3) prolonged the duration.

They suggested that not simply did this indicate that effective narcotic doses could be decreased but it also indicated that proglumide might be able to enhance the effects of other procedures, such as acupuncture, which involve endogenous opiates. (Watkins et al. 1984)

Proglumide is a nonselective CCK inhibitor that was formerly employed as an anti-ulcer medication (Hahne et al. 1981). It shows NO analgesic effects of its own.

Although proglumide is now considered to be an obsolete pharmaceutical due to changes in our understandings of ulcer etiology, it has already seen extensive pharmacological and toxicological testing proving its safety and has been approved for use in humans.

It has largely fallen into disuse but is still available in bulk via chemical houses or as a pharmaceutical in Europe and Africa sold under the trade name Milid and Milide.

Other CCK inhibitors show similar properties (Idänpään-Heikkilä et al. 1997; Xu et al. 1993). However, beyond simply having seen previous use in humans, proglumide is both inexpensive and nontoxic. (Ott 1999)

Proglumide is not some sort of magic bullet for completely eliminating the risk of tolerance development and addiction as its effects are only effective for a limited duration before tolerance to IT begins to develop. (After 8 days its effectiveness begins to wane) The work of Kellstein & Mayer 1990 suggests that successful therapeutic/maintenance applications will probably require its discontinuation for a week after each week of use. More work is needed to better define the precise parameters of its effective use for this purpose.

Despite this, proglumide has already demonstrated itself to be of value both in pain management and as an adjunct to maintaining a narcotic addiction within a larger program of harm reduction (Anonymous 2000; Ott 1999).

What is fascinating is how few drug educators, drug treatment facilities or even drug users are aware of this despite it being readily available information for nearly 20 years.

If development of tolerance and the high price of a sustained addiction are truly as serious of a problem as we all agree that they are, one can only wonder how it is that, despite the tools existing to remove or at least reduce this problem, there seems to be no interest or research except on a limited scale related to specific small areas of chronic pain management and understanding.

The current misguided approach of substituting methadone is commonly reported to actually cause MORE perceptual and thinking problems than the opiates it replaces PLUS methadone is known to cause physical damage to internal organs that are not encountered with opiate use itself.

Harm reduction approaches would benefit greatly by using proglumide as a cornerstone and making it readily available to both narcotic users and abusers.

Those who will most certainly object include organized crime and drug dealers who enjoy the obscene profits reaped from escalating drug tolerances, and possibly also the so-called drug educators that sadly often seem to be the ones most in need of some factual education.

There are many problems associated with opiate use and abuse. While the majority of these are legal in origin, the most sensible approach would be to ameliorate [or mitigate] those that arent.

Increased analgesic effectiveness and prevention of tolerance are two obvious areas where harm reduction is readily possible TODAY. Both sufferers of chronic pain and narcotic addicts stand to benefit from having their needs met and their health risks simultaneously decreased.

As this is first and foremost a health problem, the current approach of harm maximization is both counterproductive and unacceptable. To a rationale or caring mind it might even be perceived of as unethical and amoral.

Not only do sufferers of chronic pain and narcotic addicts stand to benefit from such harm reduction approaches but, by decreasing drug-associated crimes, a significant area of the true drug problem can be directly addressed, thereby benefiting society as a whole.

[long reference list not included, see: http://opioids.com/proglumide/ ]

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A randomized, double-blind, placebo-controlled safety study of high-dose dextromethorphan in methadone-maintained male inpatients

The NMDA antagonist dextromethorphan hydrobromide (DM) may be useful in the treatment of opioid dependence, particularly as a means of reducing tolerance to methadone during replacement therapy. As a prelude to clinical efficacy studies, a randomized, double-blind, placebo-controlled study examined the safety of DM in combination with methadone in inpatient, opiate-dependent volunteers. Male participants received daily methadone (50-70 mg/day) and either DM (n=10) or placebo (n=5) during the 12-day active medication phase of the study. DM participants received doses of 120, 240, and 480 mg/day in increasing order (4 days each). DM at high doses caused mild elevations of heart rate, blood pressure, temperature, and plasma bromide. However, none of these effects was clinically significant. DM caused no significant changes in respiration, pupil diameter, or subjective drug effects measured by standard scales. Participants in the DM group reported many more adverse events than did subjects on placebo (173 vs. 21), but these effects were not clinically serious. The most commonly reported side effects were sleepiness and drowsiness. Several participants reported intoxicating effects at the highest dose. Overall, DM was well-tolerated by the methadone-maintained opiate-dependent subjects studied here. These results support the further exploration of DM as an adjunct medication during methadone replacement therapy.
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12095667&dopt=Abstract