Treatment of headache, nasal congestion, gas colic, diarrhea, asthma, cough, lowering blood pressure. Components also slow down allergic reactions in the body, thus acting as antihistamines, which is essential in such respiratory conditions like asthma.
The herb stimulates the central nervous system thus increasing parameters like heart rate, blood pressure, and breathing rate, which are essential in athletic performance Hordenine has alkaloid properties, which play a part in digestion thus effecting weight management.
Unclear potentiating effect; however, this phenolic alkaloid could cause false positives in morphine immunoassays of the beer drinkers urine [13]. The herb contains compounds that are considered diuretics. Effective kidney filtration provides frequent passing of urine, thus flushing the urinary tract and resulting in a healthy system.
Possible testosterone booster. Pain reliever in traditional medicine. It was concluded that T. The essential amino acid stimulates production of dopamine, which is a chemical responsible for regulating moods in the brain and effective in the management of depression.
DLPA reacts with UV light to enhance the skin to produce more pigment, thus essential in the management of vitiligo. Components are also combined with other amino acids in the body to relieve symptoms of alcohol withdrawal. Curcumin reduces the action of chemicals responsible for inflammation.
The compound neutralizes free radicals in the body, which are responsible for abnormal growth of cells. It also stimulates other cells to produce antioxidant enzymes.
Curcumin increases the number of hormones responsible for the growth of neurons in the brain, as well as prevents degenerative processes there. The drug facilitates absorption of other drugs across membranes. It also possesses anti-inflammatory effects, thus managing pain. When used topically, the drug resolves skin breakages like herpes zoster and blisters from cancer treatment. DMSO increases absorption of opiates taken orally thus potentiating their analgesic effect in the body due to the increased availability of the binding proteins [17].
Opiates could be mixed with other substances to potentiate or increase their effects. According to [18], opiate potentiating means enhancing the effects of opioids or opiates by mixing them with another drug or substance. Although using potentiates boosts the effects of opiates, it is risky and could be associated with life-threatening side effects.
Therefore, opioid potentiators must be used with extreme caution because they are relatively safe when used as prescribed by a doctor. According to previous data, the research related to prescription or OTC drug abuse is still in its early stages, which is why the problem has yet to be solved.
However, women who use these drugs are more dependent on them than men are. According to several studies, the use of cocaine, heroin, and other abused drugs are well researched in the USA, but opioid potentiators are always overlooked.
Participants were users of these drugs from the streets. The methodology of this research indicated that methadone was extensively used We will try to describe how people from all over the nation mix opiates with different medications and various substances. More large-scale studies need to be carried out to confirm and better describe the extent of opiate enhancer misuse in the USA and elsewhere.
The first paper that was helpful in this study appeared to be one that explained issues that surrounded the abuse of opiates and their enhancers. It was also hypothesized that the increased analgesic effect of gabapentin and morphine could be contributed to by the increase in gabapentin serum concentration that results from the two medications being given together.
When combined with opiates, the risk of respiratory depression and drug-related mortality increases. Gabapentin users reported a range of subjective symptoms including euphoria, enhanced sociability, state of relaxation, sedative or opiate-like comedown, psychedelic and MDMA-like effects.
Table 4 summarizes the most recent information regarding the use of muscle relaxants in co-administration with opiates. Major effects, including boosting effect, are described in detail.
Baclofen, meprobamate, carisoprodol, chlorzoxazone, methocarbamol, tizanidine, metaxalone, orphenadrine, and cyclobenzaprine. Researchers demonstrated that the overlap that existed in the expression of opioid receptors and GABA receptors had significant importance in the interaction that existed between opioids and baclofen.
When administered together, these drugs showed synergistic activity in the production of analgesia [21]. This antagonism was implicated in its role as a muscle relaxant. Additionally, the antagonism was demonstrated to play a fundamental role in increasing the analgesic effect of opioids in the management of pain of chronic inflammatory origin, and pain that was acute in nature [22].
Authors emphasized the fact that magnesium had the ability to potentiate the activity of opioids in such a way that low doses were needed to achieve the desired effect and made it likely to be abused by opioid addicts. In addition to the above, its antagonistic role at the N-methyl-d-aspartate receptors and its abundance in the body coupled with the risks associated with the use of opioids, such as potential for tolerance development, addiction, disorders of consciousness, and constipation that are chronic among others, there was an idea to use magnesium either as an adjunct to opioids or as their replacement especially against chronic pain or against migraines [23,24].
According to the article presented, neuropathic pain that is associated with an excess stimulation of NMDA receptors obtains poor response in the use of morphine. Coadministration of an antagonist of the NMDA receptors, such as magnesium with morphine was shown not only to restore, but also to increase potency of morphine in managing the neuropathic pain [25]. Parenteral administration of magnesium sulfate in its micronized form was demonstrated to increase the antinociceptive activity of opioids in different types of pain [26].
This is a centrally acting relaxant of muscles, which combined with opioids or even benzodiazepines significantly raise effects of these drugs. Carisoprodolwas implicated as having a very high potential for abuse. The drug undergoes biotransformation in the hepatocytes through N-dealkylation and hydroxylation to form the primary metabolite, which is meprobamate. This connects and modulates the activity of GABA A receptors producing sedative-hypnotic effects within the central nervous system in a manner similar to that of the opioids [29,30].
Table 4: Summary of various muscle relaxants analyzed in previous studies. Major effects are reported. While the above drugs interact in a way that could be employed to potentially lower the amount of opioid analgesics that are used particularly against chronic pain, their augmentation or potentiation of this activity could be exploited by abusers to attain a new level of euphoric reaction.
When combined with opioids, the hypnotic effect is heightened thus it's potential for abuse. This drug is administered orally and absorption occurs within 1. The half-life of the primary metabolite is 10 hours, and this is the molecule that is responsible for sedative-hypnotic activity.
This increases its potential for abuse. Other than carisoprodol, baclofen is available in a tablet form with a strength of 10 milligrams.
This is often administered in a standard regimen of three times a day, with the strength ranging from a minimum of 5 mg to a maximum of 25 mg. After oral administration, peak plasma concentration is attained after 1 hour to 3 hours, and it is eliminated within 3 hours to 4 hours. When given with opioids, it potentiates their activity, and has the potential for inducing withdrawal symptoms. Magnesium, at a strength of mg is often given to patients, who are on opioid analgesics to lower the dose of opioids.
Because of a half-life that lasts longer than 12 hours, the tablet could be administered once daily. Being a supplement, this drug is readily available and could easily be abused when combined with opioids. Benzodiazepines are strictly controlled substances, and as such carry a risk of abuse on their own. Both opioids and benzodiazepines are able to sedate users, suppress breathing, and impair cognitive function. A description of the combined use of benzodiazepines with opiates is presented in table 5.
Diazepam was not able to inhibit the metabolism of methadone. No differences were reported in plasma levels of methadone or its metabolites.
Eleven patients, who had previously received buprenorphine, suffered sudden respiratory depression requiring manual ventilation of their lungs followed by doxapram infusion. Diazepam 40 mg significantly increased opioid subjective effects, when compared to either of the drugs alone. Table 5: Review of opioid agents and benzodiazepine use. Barbiturates are one of the most widely used potentiators for opioids.
They are central nervous system depressants, and their mode of action involves reduction of nerve activity resulting in muscle relaxation. They also reduce blood pressure, breathing and heart rate and could be habit-forming [32]. All barbiturates are known to affect gamma-aminobutyric acid, i. They are mainly administered for the treatment of headaches, seizures, and insomnia.
Examples of common barbiturates available within the United States include butalbital, phenobarbital, secobarbital, pentobarbital, butobarbital and amobarbital. The most important problem with the use of potentiators with opioids is that it results in over-sedation, which manifests through inability to respond to any form of stimuli or wake up and sometimes causes users to slip into a coma.
In addition, combination sometimes also results in changes in breathing patterns characterized by depressed breathing, which results in a state characterized by insufficient oxygen in the brain [33]. Effects of the potentiators on the euphoric impact of opioids depend on the method by which they are combined. One of the ways potentiators are taken to increase their euphoric impact is through the rectal route, whereby their effect was reported to increase by 10 percent when administered through this route.
Another methods commonly used by the abusers of opioids involves heating the opioids with the potentiates to obtain a liquid with higher concentration that is then ingested through different forms. Potentiation of opioids are linked to a larger percentage of deaths associated with the abuse of opioids.
Hypotension, confusion, tachycardia or bradycardia, false feeling of wellbeing, dizziness, headache, nausea and vomiting, weakness, dyspnea and erratic CNS stimulation symptoms [35]. Antihistamines, such as promethazine, are characterized by misuse potential among patients utilizing opioids.
As CNS depressants, the effects of these drugs could increase the risk for euphoria, intoxication, respiratory depression, and death when combined with opioids. Cimetidine: According to [39], cimetidine functions by inhibiting the cytochrome P enzymes, which are relevant in the metabolism of opioids, as well as of other drugs. Hence, it increases the duration of action of the opioids, causing an increase in the euphoric state.
This drug is a histamine H? The dosage of cimetidine varies depending on the type of disease under treatment. However, the most used dosage is mg, which is mostly available over the counter and works effectively for a maximum of a single hour [40].
This agent exhibits various effects including the risk of acute liver injury resulting from the heavy workload for the same, headache, dizziness, gynecomastia, as well as somnolence. Furthermore, in cases of overuse it could also result in diarrhea, nausea, vomiting, confusion, hallucinations, disorientation, decreased sexual ability in men, abdominal pain, easy bruising, irregular heartbeat, as well as jaundice.
Cimetidine is classified as a category B drug in pregnancy; hence, its use could be acceptable. Cimetidine mg is available over the counter, which makes this a great opiate potentiator. According to several sources, it works for about an hour. Cimetidine is likely to affect the metabolism of codeine to morphine. Diphenhydramine inhibits histamine, and also increases the analgesic, as well as the mood properties associated with opiates to a tiny degree.
Essentially, this agent inhibits a subset of CYP2D6. Diphenhydramine is considered a histamine H? The drug is fundamentally used in relieving various allergic symptoms such as itching, rash, watery eye, running nose, sneezing, and cough. The drug also is useful in the prevention and treatment of nausea, vomiting, and dizziness during motion sickness.
Diphenhydramine helps to relieve some side effects of antipsychotic medications [41]. Its onset of action is between 5 minutes to 30 minutes. The drug increases the risk of falls and over sedation in the elderly patient making it a high-risk medication. According to previous data, this agent increases the analgesic and mood properties of opiates to a small degree.
Administration of the drug alongside opiates results in the reduction of itchiness and better effects for the patient [42]. Importantly, taking more diphenhydramine than what is clinically necessary could result in hepatic injury. Promethazine is an H? In fact, it is notable that any of the other sedative anticholinergic antihistamines tends to work towards reducing various side effects of opiates and potentiation of analgesia [43].
Most importantly, this agent is strictly administered after the administration of opiates. The drug is used in allergic conditions including nausea and vomiting, postoperative sedation, motion sickness, preoperative sedation, as well as obstetric sedation.
Promethazine is administered in 25 mg orally in a frequency of every hours. It has an onset of minutes when given via intravenous route and 20 minutes when given orally. Notably, promethazine's administration using the intravenous route especially when abused could result in severe tissue injuries such as gangrene, thrombophlebitis, and burning. Consequently, the preferred method of administering this drug is deep intramuscular injection.
Moreover, an IV infusion could be given. Promethazine is considered as a category C drug in pregnancy; hence, it ought to be cautiously used in the cases where its benefits would outweigh its risks in the patient.
This drug acts by blocking the histamine receptors on the respiratory smooth muscles; hence, antagonizing their constrictor effect [45]. Furthermore, it is notable that this sedating anticholinergic antihistamine tends to work towards reducing various side effects of opiates and potentiating of analgesia.
Essentially, this medication is strictly administered after the administration of opiates. The aforementioned drug helps as a nasal decongestant, as well as in the relief of various symptoms of allergy or opiate withdrawal including running nose, sneezing, watery eyes, rash, cough, as well as itchiness exhibited in the eyes, throat, nose, and skin [46]. The dosage involves 10ml orally every hours, which does not surpass 60ml in a period of 24hours. This drug is available over the counter. Various neuropsychiatric effects of the agent include drowsiness, blurred vision, dizziness, confusion, disorientation, insomnia, sedation, as well as euphoria.
Furthermore, the drug enters breast milk and is consequently contraindicated during the period of breastfeeding. After analyzing several sources about opiate abuse, it was noted that CPM was also associated with neonatal abstinent syndrome. This drug is an H? It is notable that as any of the others sedating anticholinergic antihistamines, it tends to work towards reducing various side effects of opiates and potentiating of analgesia. The drug is applicable in the treatment, as well as prevention of motion sickness, nausea, vomiting, as well as vertigo [47].
The drug's recommended dose is 50 mg orally that should be administered thrice a day. Research postulates that the onset of action of the drug is approximated at 2 hours with a four-hour duration of action in a patient. The drug ought not to be administered concurrently with other sedatives, anticholinergics, or tranquilizers.
Cyclizine is classified under category B in pregnancy. Moreover, after analyzing several sources about opiate abuse, it was noted that cyclizine is also associated with neonatal abstinent syndrome. According to several sources, this agent is commonly used and works to enhance the effects of opiates effectively. Further, the drug is an antihistamine used in the prevention of both nausea and vomiting during pregnancy for the women who fail to respond to conservative management.
Besides, it is also essential in relieving various withdrawal symptoms. The mechanism of the prevention of morning sickness and drowsiness is not yet known [48]. Doxylamine exhibits various side effects including dry mouth, blurred vision, headache, somnolence, vertigo, fatigue, malaise, anxiety, hypersensitivity, urinary retention, as well as insomnia. These effects are exacerbated by concomitant use of doxylamine and other sedatives.
Research also indicates that women should avoid breastfeeding while undergoing therapy with this agent. Table 7 provides additional details regarding co-administration of opiates with antihistamines. Cimetidine functions by inhibiting the cytochrome P enzymes, which function in the metabolism of opioids, as well as other drugs. Hence, it increases the duration of action of the opioids causing an increased euphoric state. Dosage is mg. Risk of acute liver injury resulting from the heavy workload for the same, headache, dizziness, gynecomastia, as well as somnolence.
The drug inhibits histamine and also increasing the analgesic, as well as the mood-altering properties associated with opiates to an unusually small degree. Dry mouth, dizziness, abdominal pain, drowsiness, constipation, confusion, restlessness, irregular heartbeat, difficulty in passing urine, blurred vision, euphoria, as well as palpitation.
Works towards reducing various side effects of opiates and potentiation of analgesia. Dose is 25mg orally in a frequency of every hours and with an onset of minutes when given via intravenous route and 20 minutes when given orally. Dry mouth, constipation, drowsiness, blurred vision, sedation, confusion, disorientation, euphoria, extrapyramidal symptoms, irregular heartbeat, urinary retention as well as catatonic states.
Acts by blocking the histamine receptors on the respiratory smooth muscles; hence, antagonizing their constrictor effect. Dry mouth, constipation, drowsiness, blurred vision, dizziness, confusion, disorientation, euphoria, extrapyramidal symptoms, irregular heartbeat, hypotension, insomnia, sedation, whizzing, thickening of bronchiole secretions, as well as euphoria.
Works by blocking the H1 histamine receptor. The drug's recommended dose is 50mg orally that should be administered thrice daily. National Institutes of Health. Drug Topics. More Drug Topics. Quick Links. The prescribing of the drugs also is deeply rooted in another document, the main guide that psychiatrists and other doctors use in diagnosing mental illness -- the Diagnostic and Statistical Manual of Mental Disorders.
Revisions to the manual, including an update last year, expanded that diagnosis, which, in turn, meant more people could be treated with tranquilizers, said Allen Frances, MD , the former chair of psychiatry at Duke University. Frances also chaired the panels that developed the manual.
The benzodiazepine marketing campaign unfolded against a background of industry influence in medical practice and medical research. For example, a paper found significant financial ties between drug companies and panel members who produced the DSM-IV.
The manuals are put out by the American Psychiatric Association. For the paper, the researchers included any financial affiliations panel members had with the drug industry between the years of and Separately, benzodiazepines are mentioned favorably in a national practice guideline for treating panic disorder that also was issued by the American Psychiatric Association.
Five of the seven doctors on that panel, including its chairman, worked as speakers or consultants to drug companies that sold benzodiazepines in the 3 years prior to the publishing of the guideline, according to disclosure statements issued with the document.
This included work for Pfizer, whose drug Xanax XR, won FDA approval for the condition 3 years earlier, according to disclosure statements issued with the guideline. In an emailed statement, Darrel Regier, a physician and official with the association, said that when the guideline was issued the association required conflicts of interest to be managed by disclosure, extensive reviews of drafts, and oversight by a steering committee that had no members with financial ties to drug companies.
Regier said the diagnostic criteria for anxiety disorders did not change much from the and manuals and "would have no appreciable impact on prevalence rates. He said conflicts of interest standards have toughened since the s. Since , the association only has allowed experts without financial ties to drug companies to serve on its panels, he said.
For example, last year 61 million benzodiazepine prescriptions were written for women, compared with 29 million for men, according to data from IMS Health.
That rate may be a testament to marketing: throughout much of the later half of the 20th century, tranquilizer ads in medical journals urged clinicians to think of their female patients. To quantify the risk for mortality, we performed analyses of combined data when available and if appropriate. These analyses were conducted using statistical package R version 3. Data were analyzed using random effects models, assuming two sources of variance, within-study error and between-study error.
Separate analyses were performed for hazard ratios and incidence risk ratios. The flow chart of the PubMed search is shown in Figure 1. The search yielded 1, unique manuscripts. Five potentially eligible manuscripts were identified through reference searching i.
After careful screening of 1, titles and abstracts, full text of papers were assessed for eligibility. The majority of the manuscripts studied only the effect of opioids or benzodiazepines alone and did not specifically investigate the interaction.
These manuscripts were excluded. Finally, 29 manuscripts met the inclusion criteria and were included in this review see Figure 1. The characteristics and main findings of these studies are presented in Tables The majority of studies were retrospective cohort studies, followed by post-mortem studies and 2 prospective studies. Outcomes reporting varied accordingly: most studies reported incidences or incidence risk ratios or odds- or hazard ratios for mortality, post-mortem studies reported proportional mortality or death ratios.
Both analyses indicate that the risk for mortality is increased when opioids are concomitantly used with benzodiazepines [pooled HR 1. We will now discuss evidence for each category separately. In total, 13 manuscripts that reported on abuse or intentional misuse of opioids and sedatives, mostly benzodiazepines, were included in this review see Table 1 11 - Besides the interaction between opioids and benzodiazepines, interactions between opioids and other centrally acting substances, such as cocaine, antidepressants and alcohol were also commonly reported 12 , 13 , 15 - 18 , 20 , All studied the risk of death or severe adverse events when using opioids, benzodiazepines or both.
Overall, the majority of data show that the use of opioids with benzodiazepines or other centrally acting drugs has increased over the years, and that this drug combination increases the risk for mortality.
Data of four studies were suitable for pooled analyses. These analyses also indicated a higher risk for mortality for combined use [pooled HR 1. The results of two studies diverge from the trending findings. Abrahamsson et al. All-cause mortality however was significant in the unadjusted- and sensitivity analyses of this study. Second, Mirakbari et al. However, the methodology of this study was prone to inclusion and follow up bias In contrast, a study that reported on the treatment and outcomes after ICU admission for opioid intoxication found that patients who had also ingested benzodiazepines or amphetamines had a higher risk for mechanical ventilation and an increased length of stay A specific subgroup in this section consists of patients that are on opioid replacement therapy with buprenorphine or methadone 12 , 18 , 19 , Data from these studies indicate that benzodiazepines are involved in a significant part of fatalities in this subgroup.
Interestingly, patients on methadone replacement therapy may be at higher risk for mortality and severe adverse respiratory events when concomitantly using benzodiazepines, than patients on buprenorphine replacement therapy 12 , Finally, the manuscripts that reported on the effect of opioid combination with other CNS active substances, show an increased the risk for mortality, albeit the risks differed substantially between manuscripts and drug combination 12 , 13 , 15 - 18 , 20 , In conclusion, concomitant use of benzodiazepines or other CNS active drugs by active opioid abusers and those on opioid replacement therapy substantially increases the risk for mortality.
One manuscript was identified that reported on the use of opioids combined with benzodiazepines or antipsychotics such as haloperidol in terminally ill patients admitted to a hospice service This study found that survival in terminally ill patients was not reduced by concomitant use of an opioid with a benzodiazepine or antipsychotic. In fact, the chance of surviving longer in this setting was higher for patients that used all three classes of medication.
In addition, night-time death percentage was not increased in patients taking a drug combination. Finally, it was found that patients receiving opioid doses of more than mg oral morphine equivalents survived longer compared to patients on receiving lower doses. In conclusion, data from one study suggests that concomitant use of opioids with benzodiazepines or antipsychotics in the hospice setting may be safe.
Additional research is needed to corroborate these results. The search yielded three manuscripts that reported on the effect of opioid and sedative use in hospitalized patients 25 - The studies by Overdyk et al.
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