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Dextromethorphan Modulation of Context-Dependent Morphine Tolerance
Joanna M. Mann-Jones
Washington State University
Richard H. Ettinger
Eastern Oregon University
John Baisden and Kara Baisden
Washington State University
A series of experiments show that the expression of morphine tolerance is dependent on the context of drug administration. These conditioning effects underwent extinction when animals were repeatedly exposed to the drug context (CS) without morphine (US). Tolerance was completely reinstated (spontaneous recovery) following extinction with two very low morphine doses when administered in the original drug context. Tolerance was also easily reversed by the NMDA antagonist dextromethorphan. In a final experiment we show that morphine co administered with dextromethorphan results in morphine sensitivity, not tolerance. These results have implications for the management of chronic pain with opioids and for the effects of drug context on pain management and recovery from opioid addiction.
Morphine has long been used medicinally to relieve moderate to severe pain but its use has been restricted because of its rapidly induced tolerance and dependence. Despite efforts to develop synthetic analgesics without tolerance and dependence effects, morphine remains the drug of choice for relief of moderate to severe pain. It would be clinically desirable to improve morphine’s utility by modulating the development of tolerance. Furthermore, investigations of contributing factors to morphine dependence would be useful for developing more effective treatments for opioid dependence.
Drug tolerance shares characteristics with learned behaviors and Siegel and his colleagues (Siegel, 1976; Siegel, 1978; Siegel et al, 2000) have presented a compelling case that drug tolerance may be elicited by both contextual and drug onset cues. While associative tolerance is most frequently investigated with place conditioning procedures, other cues such as novel tastes and scents have been used to elicit morphine tolerance (Siegel et al., 2000). Associative tolerance is presumably responsible for the high rate of relapse for recovering opiate addicts (Siegel, 1999) and it may be a contributing factor to opioid overdose (Siegel, 1999, 2000).
Traditionally, conditioned responses have been thought to be similar in form to unconditioned responses elicited by unconditioned stimuli. In the case of conditioning to drug cues, however, the conditioned response is often opposite to the unconditioned response. For example, morphine administration causes analgesia, sedation, and hyperthermia while conditioned responses to morphine include hyperalgesia, increases in motor responses, and hypothermia. Presumably these conditioned responses develop as homeostatic mechanisms in response to predictable changes caused by drug effects (Siegel & Allan, 1998). Similar compensatory responses are observed following conditioning with insulin (Siegel, 1975).
Some researchers have questioned whether Pavlovian conditioning contributes to context-dependent tolerance when tolerance has not been successfully linked to the specified CS (Cepeda-Benito & Tiffany, 1996). However, Siegel (2000) has demonstrated that morphine’s drug-onset cues may provide the most reliable signal for drug administration and these cues may overshadow contextual cues. As would be predicted using the associative tolerance paradigm, administration of a small dose of morphine, rather than the accustomed larger dose, results in compensatory responses (Siegel, 2000).
Context-dependent drug tolerance shares characteristics with other learned behaviors. For example, exposure to conditioned stimuli prior to pairing these stimuli with drug cues inhibits later associations (latent inhibition, Siegel, Hinson & Krank, 1981; Siegel, 2000), the presentation of drug cues (CS’s) without the drug result in the extinction of tolerance (Siegel, Hinson & Krank, 1981; Siegel, 2000), and the presentation of a sudden stimulus can disrupt conditioned respons
MorphiDex (MS:DM) double-blind,
multiple-dose studies in chronic pain patients
Brigham & Women's Hospital,
Pain and Management Center, Boston, MA 02115, USA.
J Pain Symptom Manage 2000 Jan;19 (1 Suppl): S37-41
Preclinical and double-blind single-dose placebo-controlled studies [u]demonstrated that MorphiDex (MS:DM), a 1:1 ratio of morphine sulfate (MS) to dextromethorphan hydrobromide (DM), provides significantly greater analgesia than an equal dose of immediate release MS, with a faster onset, and a duration of > or = 8 h. The analgesic effect of MS:DM compared to MS was evaluated in 2 double-blind</u>, multiple-dose studies in 321 patients with cancer and other chronic pain: a crossover study that consisted of two 2-wk periods and a 4-wk parallel study. [u]As specified in the study protocols, patients took sufficient MS or MS:DM to achieve satisfactory pain control. In the crossover study, the MS:DM group required half as much morphine as the MS group to achieve satisfactory pain control (80 mg and 162 mg, respectively). The interval between doses and the time from the last dose of the day to the first dose of the next day were significantly longer for MS:DM compared to MS.</u> In the parallel study, MS:DM also provided pain control at a significantly lower dose. After four weeks of treatment, the mean daily dose of MS increased, while there was little change in the MS:DM mean daily dose (P = 0.025) to maintain satisfactory pain control. More patients preferred MS:DM to run-in MS than preferred MS to run-in MS (P = 0.026). The addition of DM to MS did not increase the incidence of adverse events, which were those commonly associated with opioid use. These studies confirm that MS:DM provides satisfactory pain relief but at a significantly lower morphine daily dose.
Had an relapse 10 days ago (1gr of around 60%H for 3 days) 7 days ago!
Thank god for ketamine! It is saving me life! the cravings for H is minimal, only the boredom as i don't use ketamine to get high!
But today i've used to get high, and i can tell u that i'm loving the fact that i'm so dissociated from opiates use, and just earlier today i was thinking of scoring...
The relaxed and dissociated state of mind that i am, in conjunction with ambient music that i'm listening, it seens heaven!
How could I be such a fool, and embrace again in Heroin??????
Now i can see (again) that pleasure is not an ego thing, but a thing to be harvested and seeded...
The dissociation that i get from using Ketamine/DXM after the Heroin WD is greatly rewarded to me as a person! it always make me think/feel that opiate use is an obscure an not so rewarding path of life!
Just reporting.... Stay opiates clean! It is trading a life of pleasures/goal for just one pleasure/goal! Dont....
Queen's Researchers Discover Paradox Of Pain Control; Morphine Effectiveness Restored To Between 80 And 90% Of Original Amount
(Kingston, ON) --
A surprising discovery by researchers at Queen's University could lead to the development of more effective pain-killing drugs, with fewer side effects, for terminally ill patients or people suffering from chronic diseases such as cancer or severe pain due to nerve damage.
In a paper that appears in the February 2002 Journal of Pharmacology and Experimental Therapeutics, a Queen's team led by Dr. Khem Jhamandas of the Dept. of Pharmacology and Toxicology reports the "paradoxical" findings of their research on opioid drugs such as morphine. The usefulness of these powerful drugs can diminish dramatically after their prolonged use: a phenomenon described as drug tolerance.
Jhamandas and colleagues have found that in vanishingly small doses, opioid antagonists - normally used to block the toxic effects of opioids - instead enhance pain-killing action in experimental models. As well, they discovered that the development of tolerance to morphine was inhibited, and in cases where tolerance had already developed, it was actually reversed.
"When we received the results from the first experiment, I couldn't believe it. Everything we knew up to that point indicated that it shouldn't work - but it did!" says Jhamandas.
Combining an opiate "agonist" like morphine with its "antagonist" - in this case, the drug naltrexone - is a radical approach that was inspired by suggestions in the scientific literature that opiates have both stimulatory and depressant effects, says Jhamandas. Both types of drug act on opiate receptors which are located on nerve cells that transmit pain signals. When activated by morphine, these receptors will powerfully suppress pain.
"We decided it wasn't a question of whether a drug is agonist or antagonist, but rather a question of the dose," he explains. "In higher doses, the antagonists will very effectively destroy the effects of morphine or any other opiate drug, and traditionally they have been used to reverse toxic effects of opioids. But the paradox is that, in extremely small doses, the antagonists augment morphine's analgesic action, while reducing the development of tolerance to it. Where tolerance had already been acquired, the effectiveness of morphine was restored to between 80 and 90% of its original amount."
The latter finding is particularly significant for people with chronic illnesses who require long-term use of these drugs to control their pain. As tolerance to the drugs develops and the dose is subsequently increased, there is a greater potential for harmful side effects. As well, the manifestations of physical dependency - although not a major concern in terminal illness - can also act to increase the pain, notes Jhamandas.
The multidisciplinary Queen's research team - comprising Khem Jhamandas and graduate students Kelly J. Powell and Noura S. Abul-Husn from Pharmcology and Toxicology; and Asha Jhamandas, Mary C. Olmstead, and Richard J. Benninger from Psychology - has discovered that the interaction between morphine and antagonists occurs at specific sites in the spinal cord that transmit pain signals to the brain, and has provided quantitative measures of the observed effects. This research has been funded through the Canadian Institutes of Health Research (CIHR).
Further studies could be linked to the development of more effective pain-killing drugs that require lower dosages, have fewer side effects, and remain effective with repeated use, says Khem Jhamandas. Another area that may benefit is the treatment of neuropathic pain, which results from nerve injury, and responds poorly or not at all to opiates. If the mechanisms contributing to neuropathic pain are similar to the mechanisms contributing to the development of opiate tolerance - as is being suggested by certain studies - it is possible that ultra-low doses of antagonist drugs may help to "unplug" this resistance as well, he suggests.
NMDA antagonist as (Ketamine and DXM) are opioid antagonists too! It's one of the pathways in wich is believed to prevent tolerance, but not the only one... NMDA antagonism also prevents benzodiazepine tolerance at their receptor sites, so the path of brain chemistry in here (NMDA antagonist such as Ketamine and DXM) is not only thru opioid antagonism properties...
Theres some medical literature that indicates that the NMDA receptor system may be the one related to addiction... they think that the "nowadays" receptors regarded as responsable for addiction, the Dopamine, Opiates, and Serotonin (thru less extent) systems don't quite "explain" some types of addiction.
The NMDA according to recent studies is at least responsable for not getting tolerant to various types of addicting drugs!
DXM is addictive too... It has a PAWS similar to Opiates so I have heard.
I have not gone into w/d when taking cough medicine with DXM, but will try matching 1:1 DXM with morphine to see if it helps the tolerance problem the next time I need to take my pain meds. (hopefully not for a while)
I wish I had some naltrexone to mix with it. (in very small amounts)
how do you use dxm for wds,example do you take every 4hrs,and does it really help?Bup4pain can you take hydro with it,or just use dxm for wds,back on hydro looking to get off 8 pills aday,any help would be appreciated on how to take it for wds,thank you poppy
every time you hear a bell,an angel gets its wings
"how do you use dxm for wds,example do you take every 4hrs,and does it really help?Bup4pain can you take hydro with it,or just use dxm for wds,back on hydro looking to get off 8 pills aday,any help would be appreciated on how to take it for wds,thank you poppy"
*I* did not say you could use DXM for WD
Lots of DXM info on the web, but I don't want to be "Pro" DXM for recreational purposes, so you will have to find the info yourself.
FYI recreational usage of DXM can lead to brain damage and addiction.
This thread is almost getting an alt.drugs.recreational feel to it.
Information in this forum is not monitored or provided by a medical professional. The information reflects member opinions only. Do not act on advice from these forums without first consulting a qualified medical professional. All content is copyrighted and protected by Aelius Group.