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. Works to enhance the effects of opiates. Further, the drug is an antihistamine used in the prevention of both nausea, as well as vomiting during pregnancy for the women who fail to respond to conservative management.
Dry mouth, blurred vision, abdominal pain, headache, somnolence, vertigo, fatigue, malaise, anxiety, hypersensitivity, urinary retention, as well as insomnia. In total, 11 atypical antipsychotic AA medications were approved by the Food and Drug Administration since the drug class was introduced in the s [49]. However, in the recent past, there was an increase in reports indicating the off-label use of the drugs outside areas approved by FDA.
Quetiapine, a type of AA, was identified as the most abused of the class [50]. Other than areas approved by FDA and health professionals, abusers are using the drugs in enhancing the effects of illicit substances such as marijuana or controlling the adverse effects of the substances. The goal of abusers is to self-medicate the withdrawal symptoms or using it in combination with other drugs against the directions of FDA.
Basically, the drug is misused and abused by taking it in excessive levels, and for purposes for which it is not meant. The drug has a special group of individuals that abuse it and in special places. According to, reports published between to indicated males in their 30s form the largest number of individuals abusing the drugs. Further individuals with a history of misusing anxiolytics, hypnotics, and sedatives were eight times more likely to misuse and abuse AAs.
Most of the users are prisoners, who were jailed as a result of substance abuse; and therefore, they seek ways to deal with the withdrawal symptoms they were facing after being stopped from drugs.
According to, prisoners abuse AAs to have uninterrupted sleep. In a study conducted to determine the effects ofolanzapine on morphine-induced emesis and dysregulation of sleep associated with chronic pain; it was established that the AAs decreased morphine-induced nausea and vomiting, and completely alleviated the disturbance of sleep induced by sciatic ligation of nerves [51].
They have difficulty sleeping as a result of mental illnesses they have such as anxiety, and once they find out that taking extra doses of AAs helps them to relaxn, they increase its demand in prisons. With the statistics on the upward trend every other year, concerns over misuse and abuse of AAs grew further making it necessary to put in place deterrent efforts to control the situation. Though the abusers of AAs are doing it in hideouts, misuse and abuse of the drugs are revealed through different means.
First, the drugs released to the market are not reaching the intended users as a result of most of the drugs ending up in the hands of abusers. According to the quetiapine black market in the US grew with 25 mg tablets of the drug selling for dollars. On the other hand, it was also established that the drug assumed different names while on the streets to avoid the attention of security agencies.
All these are indications of a drug being misused. The abuser takes the drug in different forms. For instance, the drugs could be taken as a tablet, an injection after dissolving the tablet and also smoked by others after combining the drug with other substances. It works faster when taken as an injection as a result of directly entering the blood system leading to immediate effect.
Misuse and abuse of the drugs lead to harmful effects that are posing a threat to the health of abusers. According to [52], misuse and abuse of AAs lead to dry mouth, abdominal pain, constipation, dizziness, asthenia, and stomach upset. Further, the drugs when used in excess lead to elevated transaminase levels, rapid weight gain and diabetes [53]. Though rarely reported, in extreme cases, abuse of AAs leads to death as a result of overdose or wrong combination with other drugs.
Clozapine and olanzapine were found to have the most extreme side effects while lurasidone, aripiprazole and ziprasidone had low risks compared to others. These effects contribute to increasing healthcare costs that became a major concern within the US healthcare industry.
Further, the abuse of these drugs was found to be addictive, which forms the basis of abusing AAs. Many side effects also led to the worries of the drug being taken off-label as a measure of control due to the rising levels of misuse. According to, there is a discussion over the unwelcome possibility of restricting access to the drugs. Though such a move would have good intentions of managing the situation that is slowly running out of control, it would serve as a serious blow to the millions of mentally ill-patients that depend on the drug in their treatment.
The drugs have been found to be quite effective, when used in the right areas as guided by FDA and by prescriptions of healthcare professionals. Many of the side effects of AAs were the result of overdose and combination with other drugs not prescribed by healthcare professionals. One of the drugs commonly combined with AAs is the opiates. The purpose for such combinations is to boost the effectiveness of opiates, which are mainly used in the treatment of medium to extreme levels of pain that may not respond well to other forms of medication.
The general observation is that when combined with other drugs, the effects experienced are more severe even though the abusers carry out the combination to boost the effectiveness of the drugs. The effects of combining AAs with opiates are harmful to the health of the abusers. Combined drugs are taken in different ways.
According to, the drugs are administered either intravenously or orally. When taken intravenously, the drugs act faster compared to when they are administered orally. Abusers prefer this way of administration, as it skips hepatic metabolism leading to higher doses being quickly absorbed into the bloodstream. Besides the two forms of administration, smoking was also utilized as a means through which abusers administer the combined drugs. According to, a case of a patient who preferred marijuana and crushed quetiapine tablets with marijuana was reported.
This was done with the hope of experiencing a relaxed night, as abusers believe, by abusing AAs they will be able to address their mental illness. However, as established in the effects of abusing AAs, the abusers are putting their health at risk.
AAs are drugs previously not considered to have the potential of abuse but have currently been subjected to misuse and abuse. Abusers of the drugs are using it to deal with withdrawal symptoms. A majority of the abusers are found in prisons, where they use the drugs for getting relaxed sleep. In other instances, the drugs are used in combination with other drugs as a way of boosting the effectiveness of the other drugs. Whether abused on their own or in combination with other drugs, side effects include weight gain or diseases such as diabetes and addiction.
In extreme cases, abuse of AAa resulted in death and is therefore generally a threat to the well being of the abusers. Increasing rates of misuse and abuse haveled to discussion of the unwelcomed move of making it difficult to access the drugs, as they are a hot product on the black market, where they are being misused.
Though such a move will be good for controlling the side effects, it will be a big concern to the millions of people with mental illnesses that depend on the drug for the treatment. Entails a review of literature with a focus on studies in which researchers assessed the effectiveness of combining morphine and amphetamine or its analog methylphenidate with the view of increasing the effectiveness of morphine in producing analgesia [54].
Authors indicate that experiments involving human and animal subjects demonstrated that combining methylphenidate or d-amphetamine with morphine results in increasing effectiveness of morphine in producing analgesia. They also mention that studies analyzed that involved human subjects indicated that analgesia produced by opioids such as morphine was enhanced by amphetamines. When cognitive ability and alertness of a patient increases, the dose of an opioid used to produce analgesia could be increased.
This provides space for increasing analgesia without fear of cognitive effects of the opioid, and this could only be achieved through the combination therapy as reported by [55] and in the literature review. The article indicates that the combination of an opioid analgesic and either methylphenidate or d-amphetamine could be used to enhance analgesia and cognition of patients with the goal of improving their quality of life, especially when the patients were going through debilitating pain that prevented them from living with the highest possible quality of life.
The second study is by [56]. However, the use of this combination resulted in multiple deaths [57]. In the history of combining an opiate with a psycho-stimulant, heroin and cocaine were the most widely used combination according to [58] and as reported.
However, methamphetamine became increasingly popular over the past few years, and as such was used in combination with opiates and other substances of abuse. Despite the rapid increase in the latter combination, research was limited in this field, and as such, the authors carried out this study to establish the interaction between opiates and methamphetamine.
They assessed interactions that are behavioral in nature between morphine and methamphetamine, while utilizing a wide range of dosages for each of these drugs. Rats were used as the animal subjects for testing these interactions. The researchers found out that a combination of morphine and methamphetamine generated behavior stimulation that was significantly higher when a comparison was made in the use of each of these drugs separately.
However, they discovered that the extent of interaction between morphine and methamphetamine depended on dosages of each drug used, and the type of behavior that was assessed.
They concluded that combining these drugs resulted in interactions, in behavior, and in a manner that was complex. They also indicated that combining morphine, opiates and methamphetamine resulted in greater effects than when each of these drugs was used separately.
The third study that is the focus of this paper was carried out by [59]. The study aim was to evaluate the prevalence and trends of concurrently using opioids and stimulants by the adults that were suffering from attention-deficit hyperactivity disorder ADHD. Researchers also intended to evaluate the factors that characterized the long-term use of this combination among these patients.
They carried out a cross-sectional study in which data was extracted for the period between the years and the year from 29 different states within the United States of America. They used multivariable models of regression in determining trends regarding the prevalence of long-term use of a combination of an opioid and a stimulant, and risk factors that led to such concurrent use. They found there was an increase in the concurrent use of an opioid and a stimulant in the long-term period among adults who had ADHD.
They also found out that the predisposing factors that led to the concurrent use of this combination, other than being 40 years or older, was being a non-Hispanic white, being a resident of the southern and northeast regions of the United States of America, and being diagnosed with substance abuse disorder. Those who were depressed had an anxiety disorder, pain that was chronic, chronic obstructive pulmonary disease, and cardiovascular conditions had the highest likelihood of using this combination.
The researchers concluded that concurrent utilization of an opiate and a stimulant combination in the long-term period among adults who were suffering from ADHD, was a common occurrence. As such, co-administration of opioids and stimulants in the long-term management of pain associated with ADHD would require prioritizing the comprehension of risks associated with this process.
The final article under consideration is an opinion paper on the need to adopt concurrent use of opioids and stimulants in relieving pain while preventing complications associated with opioid use by [60]. The author begins by indicating that morphine was historically used with great success together with dextroamphetamine to achieve greater levels of pain relief by one and a half and two times the pain-relieving effect that would normally be achieved when morphine was used alone.
Other than the use of dextroamphetamine, the article points out that cocaine and morphine were successfully used to manage pain in patients who were in agony for illnesses that were at the advanced stages as per the book by [61]. Indicated that opioids had numerous side effects that included constipation, fatigue, sedation, suppression of hormones,falls, and mental exhaustion.
Those required lowering of the dosage of opioids used while attaining pain relief. In order to do this, there was need to add a stimulant that would ensure sufficient pain relief to the patient while lowering the dose of opioids, so that they could experience as few as possible of these side effects. The question,is how this is achieved in the body. In this article, is indicated that numerous neurochemical pathways were involved in relieving pain. These pathways included the adrenergic system, gamma-aminobutyric acid GABA-nergic pathway, and the serotonergic pathway as quoted from [62].
Stimulants worked by targeting the adrenergic system with a focus on noradrenaline, while morphine and other opioids targeted the endorphin receptors. The combination of these two modalities of action ensured that a greater impact was attained in relieving pain than when each of these drugs was used alone.
Table 8 describes various effects and findings due to simultaneous use of opiates and stimulants. It exists in numerous forms. These include tablets that are meant for immediate release. These patients could also be given oral solution or a suppository of morphine that has either 10 milligrams or 20 mg of the drug. They could also be injected with the drug through various routes for acute pain. According to the reviewed articles, intravenous morphine could be given for acute pain, when an antagonist is available.
In this case, the dosing is between 2mg and 10mg for an adult weighing 70 kg in body weight. Such acute pain includes post-operative severe pain. Additionally, morphine is used to manage pain that is chronic. According to the reviewed articles, this pain could either be related to cancer or other chronic illnesses that are non-cancer related. Morphine acts through endorphin receptors, where it blocks the ascending pathways of pain and thus alters the natural response that the body has towards pain.
In this process, it generates analgesia. However, it also produces depression of the respiratory system, significant sedation, constipation, fatigue, dullness of mental activity, hormonal suppression and falls []. This is available in the strength of 5 milligrams administered in tablet form orally at an initial dose of 5mg every 24 hours or in divided doses for the treatment of attention-deficit hyperactivity disorder ADHD.
It is used in combination with opioids like morphine to produce marked analgesia, as indicated in the reviewed articles. It directly stimulates the central nervous system by causing dopamine release and the release of other catecholamines. Therefore, it augments analgesia produced by morphine or other opioids.
Table 8 : Simultaneous use of opiates and stimulants. The use of opioids brought about fears regarding their potential to increase the likelihood of the user becoming dependent or addicted to the opioid. This led to studies being conducted on the combination of other forms of central nervous stimulants and opiates like morphine. The aim of these studies was to demonstrate that such combinations help in attaining sufficient pain relief with minimal effective dose of opiates likes morphine. This not only lowers the side effects experienced when high doses of opiates are used, but also reduces the likelihood of addiction.
Other than these, the long-term effect and likelihood of use of such combinations should be assessed for its benefits and risks for either ADHD or pain. Pharmacokinetic enhancers are used to boost the effectiveness of another drug. When the two drugs are given together, the pharmacokinetic enhancer interferes with the metabolism of the other drug which allows the targeted drug to remain in the body longer and at a higher concentration. While this principle has clinical utility in many settings, it could be abused to potentiate the effects of opioids.
Below is a list of some common pharmacokinetic enhancers that could be utilized as opioid potentiators. This inhibition of CYP3A4 leads to a subsequent increase in the serum concentration of the opioid due to its decreased metabolism.
Ritonavir, atazanavir ATV , indinavir and cobicistat are a few examples of these drugs. Some authors describe HIV drugs as potentiators of opiate drugs. Medications or substances described in the articles include buprenorphine, atazanavir, methadone and antiretroviral medications [].
The majority of these articles discuss pharmacokinetic interactions between antiretroviral drugs and opiates. For instance, in their article, [74] examined drug interactions between buprenorphine and the protease inhibitors atazanavir and ritonavir.
According to the authors, HIV drugs have an effect on treating opioid dependence. Their study concluded that ATV administration for the treatment of HIV disease in opioid-dependent patients produced a pharmacokinetic interaction characterized by increased metabolite and buprenorphine concentrations.
Also, McCance-Katzsummarizes the present information regarding interactions between methadone and antiretroviral medications. According to the article , buprenorphine has a significant pharmacokinetic interaction with antiretrovirals although not a pharmacodynamic relationship; hence, simultaneous use of such drugs is unable to treat opioid-dependence in HIV-infected patients.
Studies referred to in these articles demonstrated that HIV drugs had positive effects, when used simultaneously with opiates. Also, the articles indicated that opiates were highly recommended to HIV-infected people since most of them are likely to have chronic pain.
According to the article by, HIV-infected persons were recommended to use opioid doses below the morphine milligram equivalents MMEs range to be effective and avoid the risk of overdose, which could adversely affect the patient. Drugs like methadone are said to be opioid agonists and are known to prevent opiate dependence. HIV drugs have a pharmacological effect of reducing opiate addiction.
It is clear from the articles that simultaneous use of opiates with HIV drugs help in reducing opioid dependence. Certain antifungal agents such as itraconazole, ketoconazole and posaconazole are strong inhibitors of cytochrome P enzymes. This inhibition leads to a subsequent increase in the serum concentration of the opioid due to its decreased metabolism. Medications described in the literature include: fluconazole FLC , itraconazole, voriconazole, ketoconazole, terbinafine, tolnaftate, caspofungin, micafungin, anidulafungin, nystatin and amphotericin B, and methadone.
The articles indicate that most antifungals like itraconazole are available in the form of capsules, intravenous and oral solutions. Also, fluconazole is available in capsules, tablets, powdered, or injectable forms that consist of 2 mg of fluconazole and 9 mg of sodium chloride diluents. They are used for several days ; for instance, a person takes one tablet three times a day. One of the articles discussing the pharmacological effects of antifungals on potentiating opiatesis.
According to the article, interaction of antifungals with opiates increases blood concentration of the opioids, thus, increasing their effectiveness. According to [75], antifungal drugs like azoles have inhibitory effects. Interaction between antifungal drugs and opiates could change the pharmacokinetics of the drugs.
Azole agents block the in vitro metabolism of methadone opioid. This initiates a longer presence of opiates in the body thus increasing its effectiveness. Antifungal medications have the pharmacological effect of potentiating opiates.
However, there is a significant lack of information regarding the use of these medications in opiate potentiating. Antifungal drugs have an effect of potentiating opiates by preventing opiate tolerance, as described in the article. According to their article, if antifungal drugs are used simultaneously with opioids after a patient develops drug dependence of opiates, a potentiating effect is created, thus making the opiates become more effective [76]. The authors referred to a study to determine whether use of ketoconazole increased opioid and cocaine use in methadone-maintained patients.
Findings of the study indicated the increased use of opioids on humans who used methadone when subjected to chronic ketoconazole treatment. The side effects of voriconazole included reversible disturbances in vision such as a blurred vision, bright spots or altered color discrimination [78]. Ketoconazole led to a lower incidence of failure to achieve complete resolution than was observed with placebo, but the results were statistically heterogeneous and could not be explained by subgroup analyses of dose, mode of delivery or conflict of interest [79].
Certain antibiotics such as clarithromycin are strong inhibitors of cytochrome P enzymes. These articles discuss interactions that opioids have with antibiotic drugs. According to the article, there are various antibiotics that have interactions with opioids.
From the article, it is clear that, when antibiotics are used with opioids, they increase effectiveness of the opioid drugs, as well as treating the opioid-related adverse effects. The article clarifies that almost all antibiotics, when combined with opioids, have a potentiating effect.
The article gives an example of warfarin, which could be potentiated with antibiotics by inhibiting intestinal flora that produces vitamin K. Also, when warfarin is combined with antibiotics, hepatic metabolism of warfarin is inhibited, thus, increasing its effectiveness.
Interaction of opioid analgesics and other drugs results in pharmacological effects that rely on the interacting agents, and the mode of administration. The study presented confirms that antibiotics are often combined with opioids in patients undergoing surgical procedures to increase the strength of the opioids in relieving pain.
An example is erythromycin, which increases the effect of opioids when combined with the drugs. The review by [81] reveals that antibiotics have no early effect on pain, and a slight effect on pain in the days following.
There was only a modest effect with a number of children with tympanic perforations, contralateral otitis episodes and abnormal tympanometry findings at two to four weeks and at six to eight weeks, compared with placebo in children with acute otitis media AOM. However, when combined with opioids, the rate at which they relieve pain increases.
This clearly indicates that antibiotics have a potentiating effect on opioids. Furthermore, supports opiate potentiation by the antibiotics. According to the article, antibiotics inhibit CYP34A thus having a similar mechanism of action as antifungals, which produces similar potentiation effects. As a result, the effect of the opioid drug increases. However, when used simultaneously, there appears to be an adverse reaction such as an overdose; and it could result in drug abuse, which could further be considered hazardous.
Table 9 summarizes existing findings on simultaneous use of these medications. Doses or pattern of use of these medications differ depending on the drug itself. For example, atazanavir is not orally taken, instead the patient is injected with it two times a day. Raltegravir is administered two times a day. Nonetheless, the number of drugs taken by HIV patients was reduced from about 20 tablets a day in to one tablet in The recommended dose for buprenorphine and methadone should be below the morphine milligram equivalents MMEs range.
ATV administration for the treatment of HIV disease in opioid-depended produces a pharmacokinetic interaction characterized by increased metabolite and buprenorphine concentrations. Medications or substances described in articles: fluconazole FLC , itraconazole, voriconazole, ketoconazole, terbinafine, tolnaftate, caspofungin, micafungin, anidulafungin, nystatin and amphotericin B, and methadone. Most antifungals like itraconazole are available in the form of capsules, intravenous and oral solutions.
Also, fluconazole is available in capsules, tablet, powdered or injectable forms that consist of 2 mg of fluconazole and 9 mg of sodium chloride diluent. They are used for several days, for instance; a person takes one tablet three times a day. Interaction of antifungals with opiates increases blood concentration of the opioid, thus increasing their effectiveness. Antifungal drugs like azoles have an inhibitory effect. Also, interaction between antifungal drugs and opiates could change the pharmacokinetics of the drugs.
Lastly, when antifungal drugs are used with opiates, they could block an enzyme CYP3A4 from assisting to metabolize the opioid drug; therefore, increasing the amount of the drug in the blood.
Medications or substances described in articles include codeine, oxycodone, erythromycin, phenytoin, carbamazepine, ciprofloxacin, aspirin and barbiturates. Erythromycin increases and rifampicin decreases the effects of opioids, while cimetidine could enhance the effects of opioids by increasing their duration of action.
Also, carbamazepine, phenytoin and barbiturates could enhance the metabolism of opioids that rely on hepatic metabolism. Ciprofloxacin increases the effect of warfarin. Also, ciprofloxacin inhibits warfarin's metabolism ; may alternate opiate metabolism [82]. Table 9 : Pharmacokinetic enhancers and opiates potentiation. According to different studies and patient reports about the effects of tropicamide, these are remarkable in claiming the increased efficacy of heroin along with decreasing and delayed withdrawal symptoms.
For example, Spangolo et al. She reported injecting tropicamide, because it attenuated symptoms and signs of opiate withdrawal, and also had hallucinogenic and euphorigenic effects. Acute tropicamide intoxication could lead to anticholinergic syndrome, hyperthermia, tremors and convulsions. Chronic tropicamide-related problems include cardiovascular toxicity, psychosis, renal or liver failure, severe weight loss and infections [83].
Sharma et al. The study reported that co-administration of naproxen non-selective COX inhibitor with opioids potentiated the antinociceptive effect. It appears that inhibition of COX-1, rather than COX-2, plays an important role in synergistic antinociceptive effects of combination therapy. This particular study was selected because it introduces the same idea as that is used by the patients abusing the opioids.
The main limitation of the study was in the fact that it was conducted on animals, rather than on human beings [84]. The main reason why people are potentiating opiates is to make the drugs effect more powerful. Additionally, the literature overview indicates that drug providers and other professionals, who are allowed to prescribe opiates, provide most of the potentiating drugs to users.
Use of opioid enhancers represents a serious health risk. More large-scale studies are needed to be carried out to confirm and better describe the extent of opiate enhancer misuse in the USA and elsewhere. Specific prevention programs should be implemented for the general population, as well as for the high-risk population of poly drug abusers. Health and other professionals should be rapidly informed about this new and alarming trend in misuse. As a part of the recommendation, it is essential for the American healthcare systems to review, the way these potentiating drugs should be prescribed to patients, especially to those below the age of 18 years.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI: Abstract Opiates are generally indicated for the treatment of various pain syndromes; however, if alternate treatments have been exhausted and a physician elects to prescribe opioids, then both the physician and patient should be aware of the risks associated with use.
Diphenhydramine; Herbs; Hydrocodone; Opioid abuse. Figure 1: Opiate metabolism. NMDA antagonists Memantine DXM dextromethorphan Magnesium sulfate Memantine blocks the effects of glutamate, a neurotransmitter in the brain that leads to neuronal excitability and overstimulation of neurons.
Muscle-relaxants Magnesium Orphenadrine Cyclobenzaprine Carisoprodol Baclofen Magnesium acts by binding to and lowering the activity of NMDA receptors through blocking of the calcium channels that are coupled with these receptors.
Cyclobenzaprine is a centrally acting skeletal muscle relaxant. Antimalarial medications Quinine Quinine inhibits nucleic acid synthesis, protein synthesis, and glycolysis inPlasmodium falciparum and could bind with hemazoin in parasitized erythrocytes.
Opiate receptor agents Loperamide Propoxyphene DXM dextromethorphan Loperamide : agonist at mu-opioid receptors; slows gut motility. COX inhibitors Naproxen Reversibly inhibits cyclooxygenase-1 and 2 COX-1 and 2 enzymes, which results in decreased formation of prostaglandin precursors. Table 2 : Most common opiate potentiators. Rhodiola Decreases stress, improves brain function, treatment of depression, management of diabetes and cancer.
Rhodiolarosea L. Ashwagandha Management of stress, anxiety, attention deficit disorder, bipolar disorder, diabetes, high cholesterol levels, male infertility.
Stimulates cell apoptosis. Decreases stress and anxiety. Boosts testosterone. Stimulates the breakdown of cholesterol and triglycerides. Clinical studies show potentiation and tolerance reversal [11]. Black seed Nigella sativa Treatment of headache, nasal congestion, gas colic, diarrhea, asthma, cough, lowering blood pressure. Black seed stimulates production of white blood cells. This substance was reported to be a potentiator, but confirmedmechanisms are missing. Hordenine Athletic performance, weight loss.
Tribulusterrestris Enhancing libido, keeping the urinary tract healthy and reducing swelling. Mild MAO-B inhibitor. DLPA Treatment of vitiligo, depression, pain, alcohol withdrawal 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.
Markedly potentiates opiate analgesia [15]. According to various reports, 2g taken with piperine potentiates the potentiator [16]. Dimethylsulfoxide DMSO Treatment of bladder inflammation, skin conditions, management of inflammatory pain. Table 3: Other medications and herbal medicines. General overview Opiates could be mixed with other substances to potentiate or increase their effects. Gabapentinoids 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.
Muscle relaxant Opiate agent Description Baclofen, meprobamate, carisoprodol, chlorzoxazone, methocarbamol, tizanidine, metaxalone, orphenadrine, and cyclobenzaprine. Baclofen Fentanyl, oxycodone, morphine, and buprenorphine 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. Magnesium sulfate Various 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.
Magnesium sulfate Morphine 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. Magnesium sulfate Morphine Tramadol Oxycodone Parenteral administration of magnesium sulfate in its micronized form was demonstrated to increase the antinociceptive activity of opioids in different types of pain [26].
Diazepam Buprenorphine Fentanyl Eleven patients, who had previously received buprenorphine, suffered sudden respiratory depression requiring manual ventilation of their lungs followed by doxapram infusion. No evidence of drug-drug interaction between the two agents. Increased sleeping time [36]. Phenobarbital with morphine 60mg Reduced short-term tolerance to morphine [37]. Opiate of Potentiation Medication Used as Potentiation Mechanism of Action and Dosages Effects Morphine, fentanyl and nalbuphine Cimetidine Cimetidine functions by inhibiting the cytochrome P enzymes, which function in the metabolism of opioids, as well as other drugs.
Anafranil —A Tricyclic antidepressant that could potentiate opiates. DXM is a whole potent analgesic drug itself. Dosage is 30mg of DXM a good half hour.
This chemical is highly illegal in some countries only available as cough syrup in some due to potential for abuse. There is ample scientific evidence on this one but remains controversial.
Proglumide and Memantine — Proglumide naturally enhances opiate effects as well as reverses tolerance over time. These are tolerance reversal and prevention agents and I would not classify them as strictly potentiators though they can be used in that way.
Magnesium — Efficacy is unknown as there are multiple forms of Magnesium. Magnesium also acts as an NMDA antagonist. Magnesium Maleate is usually the one quoted as having effects. If anything it is good at calming nerves and reducing things like bruxism.
Loperamide Immodium — 2mg. A little unclear whether this works or not. The theory is that loperamide occupy gut opiate receptors, thus freeing up more opiates to act on the brain. Seems to enhance analgesic effects more than mood effects, though. Orphenadrine — Anticholinergic used to treat muscle spasms, potentiator because it is strong anticholinergics. Cyclobenzaprine — Same as above. Carisoprodol Soma — Same as above. Propoxyphene — Huge potentiator of opium, but for other opiates it is unknown.
Naproxen — Non-selective COX inhibitor. Adds analgesia and increases mood effects. COX inhibitors reliably have shown in studies and patents to potentiate opiate effects. Other drugs of the same class may have effects also. Also an NMDA antagonist too. Baking Soda — Only necessary for oral ingestion affects PH of the stomach to allow more opiates to be absorbed into the blood.
Rhodiola and Ashwagandha — Clinical studies show potentiation and tolerance reversal. We have some other herbs listed in this blog post. And there are probably others that can potentiate opiates, its hard to include everything ever. Black Seed Oil cumin seed. Hordenine very minute amounts, 5 — 20mg, even. Curcumin around 2g taken with Piperine — this potentiates the potentiator. I hope you're not planning on taking all of that stuff at once.
That is a recipe for disaster even if you don't take opiates as well. You should not be combining that many drugs, let alone drugs with known interactions. Taking a CYP inhibitor with an opiate you are tolerant to is relatively safe. When you mix CYP pathway drugs you run the risk of dangerous interactions. Essentially you can saturate this liver enzyme pathway that breaks down the drugs in your blood stream.
When you are simply saturating it with the goal of increasing the blood-plasma levels of a single drug like an opiate, the results are going to be relatively predictable. Just mixing 2 drugs that are metabolized through CYP enzymes is going to have unpedictable results. With both drugs increasing their potency due to the saturation of this metabolic pathway. If you add a CYP inhibitor to the mix you make things exponentially more dangerous as you'll increase the effect of both drugs you've taken dramatically.
You don't want to also add a CYP since they are already both being metabolized on that pathway. Both already potentiate each-other because of CYP interaction. And adding an inhibitor is just crazy.
SO please. Mixing one or two in this fashion is dangerous enough, mixing is 'effing psychotic. Really I think anything that is psycho-active shouldn't be considered a 'potentiator'. Potentiator' should be restricted to drugs that either effect tolerance or metabolism. CYP enzyme inhibitors effect metabolism. Stuff like ultra-low-dose naltrexone and agmatine effect tolerance. They shouldn't really be considered a 'potentiator'. If you are taking a benzodiazepine, soma, alcohol, or NMDA antagonist you aren't 'potentiating'.
You are simply enjoying the effect of multi-drug intoxication.
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