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Opioids are drugs that act on the opioid receptors in the brain, spinal cord, gut, and other locations throughout the body. There are four main subreceptor types that have different actions. Ultimately, the mu and kappa subtypes are the most important, being responsible for pain relief but also responsible for many of the side effects including nausea, respiratory difficulties, and euphoria.
There are naturally occurring opioids, more accurately called opiates because they derive from the opium poppy. These include morphine and codeine. There are also semisynthetic opioids, made from thebaine, a component of opium. These semisynthetic opioids include heroin, hydrocodone, oxycodone, hydromorphone, buprenorphine and oxycodone. Then there are the synthetic opioids that include fentanyl, meperidine (Demerol), nalbuphine, butorphanol, pentazocine (Talwin), methadone, LAAM, and others. All of the opiates, semisynthetic opioids, and synthetic opioids act on the same receptors in the brain and spinal cord, but to different extents. The opioids after entering the body (by snorting, huffing, smoking, subcutaneous/intramuscular/intravenous injections, transcutaneous, transbuccal, rectal, etc.) then circulate throughout the body carried by the blood then "bind" to the receptors. Some bind much tighter than others to the receptors, and their strength and some of their longevity of effect is due to how tightly they bind to the receptors. Another factor in how much effect the drug has is based on how much is in the blood stream. Intravenous gives the highest levels followed by smoking then snorting then huffing. The lowest levels are usually seen with transcutaneous (like duragesic patches). The half life of the drug is based on its redistribution into the fat, muscle, and different organs of the body and on how fast the liver metabolizes the drug to make it more easily pass out of the body. Liver function and kidney function play a large role in drug metabolism and elimination, respectively. If liver metabolism is poor (hepatitis, other drugs affecting the liver, etc), then the drug builds up in the body and is stored in the tissues. In some cases such as methadone, the drug cannot normally be easily metabolized by the liver, and it accumulates in the bone marrow, lungs, and liver. The half life of methadone is around 39 hours but may be much longer in case of liver dysfunction.
All the opioids cause a release of dopamine, acting to stimulate the pleasure centers of the brain. Other drugs that activate dopamine include alcohol, cocaine, and methamphetamine. Sex and other pleasurable experiences also create dopamine in the brain. The extent of addiction is in part due to the amount of dopamine being released by the different drugs. Methamphetamine releases a lot of dopamine making it very addictive. Heroin is seeming more addictive than other opioids because of the much higher ability to rapidly cross into the brain, leading to levels of opioids on the receptors that are very high.
Properties of Opioids
Side Effects- Most opioids share similar side effects including dose dependent effects of constipation, nausea, vomiting, respiratory depression, sedation, mental slowing, grogginess, itching, urinary retention.
Tolerance- Patients starting continuous daily doses of opioids including heroin will rapidly develop tolerance to some of the side effects above within a week, but they also develop tolerance to the pain killing effects. Once a person has been taking these drugs several times a day for two weeks, they have to escalate the dosages in order to achieve the same pain killing effects. If the dosages are escalated to above 40mg a day then most patients will have mild to moderate withdrawal syndrome, that includes increased pain that may be confused with increased pain from the original injury or surgery. The tolerance to most side effects, except constipation, increases with gradual dosage escalations to the point some patients can tolerate thousands of milligrams a day of these medications. (In an opioid naive person, a hundred milligrams a day of these drugs can kill).
Overdose- The number dying from overdose of prescription opioids and heroin in the US continues to accelerate through 2015 based on available data (more than 18,500 per year). Once tolerance develops, people no longer get the "high" from opioids, and they begin to add other drugs or other methods of administration in order to try to achieve euphoria. Multiple drugs used in overdose are the rule rather than the exception with alcohol being found in 22% and benzodiazepines in 40-50% of opioid overdoses. Only 25% of drug overdoses with opioids are using opioids alone. Some of the reasons opioid overdoses continue to escalate include the method of use of these drugs. Prescription opioids are ground up between spoons and injected after adding water, or are snorted- both methods give a more rapid increase in blood concentrations resulting in a greater "high", but also taking a person perilously close to unconsciousness with respiratory arrest. Heroin is available in such a pure form now that it can be smoked in addition to the previous methods of administration IV injection or snorting or huffing (inhaling the drug into the lungs). When opioids are taken intravenously, the highest and most rapid blood levels are achieved, therefore the biggest "high". Oxycodone intravenous compared to intranasal routes show the time of maximum concentration in the blood is 7 minutes for IV vs 65 minutes for intranasal vs 3.7 hours for oral. The concentrations achieved with intravenous dosing is approximately 3 times higher than intranasal and 6 times higher than oral short acting (Roxicodone) dosing and 7 times higher than Oxycontin (sustained release oxycodone). (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-011_Roxicodone_BioPharmr.pdf, J Clin Pharmacol. 2012 Apr; 52(4): 600–606). It is difficult to smoke oxycodone because of the additives, but heroin can be smoked. For heroin, IV vs huffed (inhaled), the IV route results in 5 times the blood concentration than huffing or snorting. Overdose therefore is partially dependent on the route of administration of the drugs and the dependent maximum drug level obtained in the bloodstream.
Intravenous > smoked > snorted/huffed > oral short acting > oral long acting > rectal
Overdose may result in any of the spectrum of symptoms: slow, shallow breathing, clammy skin, blue lips, convulsions, extreme somnolence, severe respiratory depression (breathing 2-5 times per minute compared to the normal 12-20), respiratory arrest (stop breathing), circulatory collapse (severe lowering of blood pressure), cardiac arrest (heart stoppage), coma, and death. If naloxone (intranasal spray or intramuscular or IV) is administered rapidly enough before cardiac arrest occurs, it is possible the person may immediately awaken and begin breathing again, but the person needs to immediately be taken to the emergency department since the person may re-narcotize and stop breathing again in 15 minutes. Naloxone only lasts 15 minutes.
Withdrawal Syndrome- The symptoms, severity, and timing of withdrawal syndrome are dependent on the dosage, whether tolerance has developed, the specific opioid, and what other medications are being taken. Withdrawal syndrome is what addicts call "getting sick", and is the most dreaded effect of addiction. In fact, most addicted people no longer "get high" from the opioid drugs they are taking- that sensation has long passed: they are simply trying to avoid going into withdrawal everyday and therefore continue taking opioids. The weaker opioids, codeine, tramadol, butorphanol, nalbuphine have very mild withdrawal symptoms that are limited to 1-2 days. The more potent mu opioids (oxycodone, morphine, oxymorphone, hydromorphone, hydrocodone) at low doses may have minimal withdrawal, but if taken at the equivalent of 40-200+ mg/day tend to have withdrawal symptoms beginning within 3-6 hours for potent short acting drugs, but not until up to 30 hours for long acting opioids (e.g. Avinza, Kadian, etc.) of the clinical timeframe of the drug. The withdrawal symptoms in most people become progressively worse days 1-3, peaking at 72 hours then gradually improve over the first week. For methadone that is stored in the body for a month after stopping the drug, the withdrawal symptoms may continue to persist for a month. High doses being taken for months to years will produce much more severe withdrawal syndrome if suddenly discontinued. Those dependent on these drugs may very gradually reduce the dosage at 5-10% reductions per week, developing only very mild withdrawal symptoms, however many going into withdrawal acutely have no choice due to an interruption in supply. Early symptoms of withdrawal may occur in a different order and may not include all these for an individual patient: tearing, running nose, yawning, muscle aches. The symptoms then progress to sweats (profusely), abdominal pain, severe anxiety, gooseflesh, hair on the arms standing up, racing heart, high blood pressure, and fever. Severe nausea, vomiting and diarrhea occur with profound drug craving, and depression may occur. The patient may become so dysfunctional they have to miss work for several days, and will do virtually anything to obtain any opioid to stop the withdrawal symptoms. Many will smoke marijuana, use methamphetamine, benzodiazepines, kratom, or ibugaine to try to stop some of the symptoms. Because the retching and vomiting can be so severe, there have been a few cases of esophageal rupture and severe dehydration/electrolyte disturbances. The most dangerous situation is for those with untreated or untreatable coronary artery disease, who may develop a heart attack during withdrawal.
There are several medications used to treat the symptoms of withdrawal but only another opioid can stop all the symptoms of withdrawal within minutes.
Withdrawal Treatment
Pregabalin (Lyrica) up to 600mg a day for 6 days plus symptom therapy was found to be superior to clonidine up to 600 micrograms a day for 6 days plus symptom therapy. 79% of the pregabalin group finished the regimen while only 47% of the clonidine group finished. The pregabalin group had significantly less craving, depression, and anxiety. Zh Nevrol Psikhiatr Im S S Korsakova. 2016;116(7):29-36
Ondansetron (Zofran) is preferred over phenergan for the treatment of nausea/vomiting during opioid withdrawal due to lack of sedation and that 12 of 13 objective signs of withdrawal are controlled during an opioid taper when using ondansetron, but did not alter subjective symptoms. However in mouse models, higher dosages of ondansetron eliminated virtually all symptoms of withdrawal. Zofran ODT sublingual tablets allow absorption of the drug even when having vomiting or retching and typically are administered at 8mg twice a day. Higher dosages may significantly improve multiple signs and symptoms of withdrawal from opioids.
Clonidine (Catapress) is used primarily as a blood pressure medicine in the US but is also used off label for opioid withdrawal. Compared to placebo, there is moderate evidence clonidine reduces severe withdrawal symptoms and that patients are more likely to complete the program of withdrawal compared to placebo. Also the severity of symptoms are not significantly different when sudden cessation of methadone is combined with clonidine compared to a gradual taper of methadone, yet the taper requires a much longer period of time. (Cochrane Database Syst Rev. 2016 May 3;(5) Clonidine reduces the symptoms of sweats, tearing, elevation of blood pressure, restlessness, and feeling sick during opioid withdrawal.
Adding amantadine 100mg BID to clonidine (0.4-1.2mg/day) plus clonazepam 1mg BID reduced the withdrawal symptoms by another 33%. (Iran J Psychiatry. 2014 Jul; 9(3): 142–146)
Adding dextromethorphan (found in cough syrup) to clonidine/lorazepam/flurazepam/loperamide withdrawal regimen improved withdraw symptoms from heroin from day 3-6. (J Clin Psychopharmacol. 2014 Aug;34(4):508-12). In another trial, compared to clonidine 0.4-1.2mg per day, the addition of dextromethorphan 300mg/day reduced the withdrawal symptoms by 20% on day 2, 40% on day 3, and 50% on day 4. (ISRN Psychiatry. 2013 Jun 20;2013:546030)
Adding low dose naltrexone (0.125-0.25mg/day) to clonidine (0.1-0.2mg Q6H) during a methadone taper significantly improved retention of patients in the taper program from 50% to 85%, and significantly reduced intensity of the symptoms of shaking, anxiety, bone and muscle aches, restlessness, and craving, as well as tearing, runny nose, and sweating compared with the clonidine only patients. (Am J Drug Alcohol Abuse. 2012 May;38(3):200-5) Indeed, a Cochrane review found a methadone taper plus low dose naltrexone was superior to clonidine (Cochrane Database Syst Rev. 2010 Jan 20;(1):CD002022)
5-HTP (an over the counter supplement) has been used to treat the muscle spasms from withdrawal using 200mg the first night then 100mg each night thereafter for 10 days. (Pain Physician. 2015 May-Jun;18(3):E417-20
Pramipexole (Mirapex) has similarly successfully been used to treat muscle restlessness during opioid withdrawal (Am J Addict. 2014 Sep-Oct;23(5):475-7)
Buprenorphine/naloxone is significantly more effective than clonidine in reducing withdrawal symptoms (COWS) from acute opioid withdrawal syndrome from day 3 onward. Craving for opioids was much better with buprenorphine/naloxone beginning day 2. J Clin Diagn Res. 2015 Jan;9(1):FC01-4
Buprenorphine is more rapidly effective than the use of methadone taper in preventing opioid withdrawal syndrome Cochrane Database Syst Rev. 2009 Jul 8;(3):CD002025
Tramadol was more effective in preventing sweating, restlessness, aches, runny nose, GI upset, yawning, anxiety and goose skin compared to clonidine in treating sudden withdrawal from heroin. (Asian J Psychiatr. 2010 Dec;3(4):237-9) HOWEVER, TRAMADOL CANNOT BE LEGALLY PRESCRIBED IN THE US FOR THE TREATMENT OF DETOXIFICATION OR MAINTENANCE.
Symptomatic treatment:
Diarrhea-loperamide(Immodium), dicyclomine (Bentyl), hyoscyamine (Anaspaz), amitriptylene (Elavil), cyclobenzaprine (Flexeril)
Nausea- ondansetron (Zofran), promethazine (Phenergan), prochlorperizine (Compazine)
Anxiety- acute treatment is with clonazepam or buspirone (Buspar) or hydroxyzine (Vistaril)
Some of the opioids used in the US-
Heroin- developed by Bayer in 1897, this drug was initially marketed as non-addictive. It is 2-4 times as potent as morphine, is legally used in Britain in labor epidural catheter infusions for labor pain and in Switzerland and a few other countries as an addiction maintenance drug. In the US, there is no medical use for the drug and it is considered a Schedule I (highly addictive without a legitimate medical use) in the US, subject to confiscation and arrests of those possessing it. In the US it is a white powder or more often a brownish powder (due to impurities). Heroin is snorted, huffed, smoked or injected. When taken orally, the effect is much less pronounced, so most addicts use it via snorting or IV. Like other opioids, tolerance quickly develops requiring increasing doses to the point the person no longer gets high from the drug (even spending $100-150 per day on the drug), but the person continues to use it to avoid withdrawal effects.
Fentanyl- a synthetic drug developed in the 1960s that is 80 times as potent as morphine. Usually for pain control of non-malignant pain it is available as a patch only that is difficult to extract the fentanyl. However fentanyl powder (pure white) is used by drug dealers to lace the heroin they sell to encourage repeat business. Unfortunately, the drug is so powerful that one use of the fentanyl laced heroin can stop the breathing causing death. Fentanyl is also produced in a variety of forms for the treatment of cancer pain only.
Oxymorphone- also known as Opana ER or Opana IR is a semisynthetic drug 3 times as potent as morphine, and is frequently crushed and snorted or injected in water. It has resulted in many deaths used in this form.
Oxycodone- also known as Roxicodone 15 or 30mg or Percocet (mixed with tylenol) or Oxycontin are commonly used forms of the drug snorted or injected, although the Oxycontin has a "glue" like matrix that stops up the nasal passages and makes it nearly impossible to dissolve the drug. Oxycontin was the drug of choice for addiction prior to it being reformulated. Percocet is sometimes dissolved and injected or Roxicodone (or generic oxycodone) but they have excipients (fillers) that constitute around 50-75% of the weight of the pill and these fillers can lodge in the lungs and small blood vessels. Oxycodone is about 1 and 1/2 times as potent as morphine and is a semisynthetic drug.
Hydromorphone- also known as Dilaudid, is a semisynthetic drug about 4-5 times as potent as morphine snorted or orally but up to 8-10 times as potent when given intravenously. It is available as a pill (most common) or as an injectable drug.
Hydrocodone- is the most prescribed drug of all classes of all drugs in America. It is a semisynthetic drug equipotent to morphine and is available in a pill form mixed with tylenol (Norco, Vicodin up to 10mg per pill ), with ibuprofen (Vicoprofen 7.5mg per pill), or as an extended release drug (Hysingla up to 120mg per pill, Zohydro up to 50mg per pill). The extended release forms are abuse resistant (difficult to snort or inject). Hydrocodone is also the most abused drug in America and the most overprescribed. 96% of all hydrocodone in the world is consumed by Americans.
Morphine- is a naturally occurring opiate, obtained mainly from the opium poppy (Papaver somniferum)
It was first isolated from the soup of other drugs in the poppy in 1803 by Serturner. However it was not used widely until the 1830s and 40s, and was used extensively in the Civil War. Initially it was used to cure opium addiction (worked very well) but then the patients were addicted to morphine. Morphine is available as 15 and 30mg instant release and up to 200mg extended release. There are several brands of extended release morphine including Embedda, MS Contin, Exalgo, Avinza, etc. Morphine consists up to 22% of the weight content of the poppy pulp. In some countries other parts of the plant other than the poppy bulbs are used to obtain morphine.
Codeine- is only about 1/6 the potency of morphine, and is very constipating, and causes significant gastric distress in some people. It was widely used in the early 20th century but is only rarely used now given the large number of other more potent medications available. It is available as T3 (Tylenol #3 containing 30mg of codeine), T4 (Tylenol #4 with 60mg of codeine). It is a naturally occurring opiate from the opium poppy.
Methadone- or Dolophine is a synthetic drug made by German scientists just before World War II. It has a very long half life in the body and can be detected a month later after stopping its use. For pain and euphoria, it lasts only 6 hours. It is a dangerous drug, resulting in a much higher percentage of overdoses compared to any other opioid, being only 2% of the opioid prescribed but resulting in 30% of the opioid related deaths. It is an exponential increase with side effects and risk such that doubling the dose will result in four times the risk of respiratory depression (stopping breathing). Most deaths from methadone occur in the first 10 days of use. Higher doses are particularly dangerous, especially over 30 mg. Most doctors are aware that they should not start patients on more than 10-20mg a day. It should not be used for pain control but only for methadone maintenance due to dose related deaths in pain patients. Methadone is used up to 300mg a day given all at once in very tolerant patients in methadone treatment centers. Giving even 1/6 of this amount at first would kill most of those starting on the drug. Withdrawal from methadone is complete in about 4-6 weeks on a taper but long term symptoms persist (dysphoria, fatigue, insomnia and irritability), for 6 to 8 months (Dialogues Clin Neurosci. 2007 Dec; 9(4): 455–470)
Desomorphine- also called krokodyl, because of the resemblence of the skin to crocodyle scales as the skin sluffs off due to infection and reaction due to impure chemicals from the kitchen being used to make the drug. Most people starting on this drug are dead within 2 years due to overwhelming infection. It is a Schedule I drug (illegal) in the US, is made in the kitchen from codeine, but since codeine is rarely prescribed in the US, its use is very small. It is a semisynthetic drug.
Pentazocine- or Talwin NX is weaker than morphine and occupies the sigma opioid receptor instead of the mu or kappa receptors as the other opioids. Overdose potential is small and limited by hallucinations when taking the pills in excess.
Meperidine- or Demerol is weaker than morphine, approximately 1/10 the potency. It is also a local anesthetic and getting too much can result in cardiac arrhythmias. It is only uncommonly used in the US anymore, and is available as pills or IV injectable or IM injectable. It is a synthetic drug.
Buprenorphine- (Subutex, generic buprenorphine, Butrans patch, Bunavail, Suboxone, etc.) is available in several forms including IV injectable, sublingual film or transbuccal form. The only forms approved for treating addiction are Subutex (pure sublingual buprenorphine pills), Suboxone (sublingual buprenorphine films with naloxone to prevent IV injecting the drug- will cause withdrawal if injected). It is a semi-synthetic drug made from the same precursor (thebane) as hydrocodone and oxycodone, that is unique as an agonist/antagonist drug. If a person has heroin on board, taking Suboxone or Subutex may precipitate withdrawal syndrome. If the Suboxone or Subutex are already on board and the person takes heroin or prescription opioids, not much happens at all- the heroin and prescription opioid effect are severely blunted. There is a ceiling effect on receptor activation, significantly reducing the potential for overdose deaths with this drug. 32mg a day has no more effect than 16mg a day due to the ceiling effect. See the subtab on buprenorphine for more information.
The amounts of buprenorphine in different products vary. Suboxone 2-8mg per film, Bunavail 2.1mg-6.3mg per film, Zubsolv 1.4-5.7mg tablets all have the same amount of buprenorphine delivered to the body due to differing availabilities from each product. So Suboxone 8mg = Bunavail 6.3mg = Zubsolv 5.7mg. Butrans patches have been used as a substitute for IV opioid use, but these are under patent protection in the US and are therefore extraordinarily expensive at this time (Indian J Psychiatry. 2016 Apr-Jun; 58(2): 152–156). Belbuca is a film of buprenorphine approved for pain control and comes in dosages of 0.075mg to 0.9mg dosages, that theoretically could be used for addiction treatment, however these are also under patent and cost 14 times as much as generic buprenorphine tablets.
Tapentadol- or Nucynta (brand name). One of the newest opioids approved in 2008 by the FDA, this mu opioid agonist has its primary effects on this opioid receptor and on inhibiting the reuptake of norepinephrine. It has only weak effects on serotonin reuptake, and has no active metabolites. It is a Schedule II controlled substance, however, seems to have very few recorded cases of overdose deaths due to the drug. It is considered to be a weak to moderate strength opioid. Nucynta is available in dosages of 50, 75, 100mg and Nucynta ER in 50, 100, 150, 200, 250mg. It is 40% the potency of morphine.
Tramadol- or Ultram (brand name). Ultram was approved for the treatment of pain by the FDA in 1995 but until 2014, it was not a controlled substance. Many physicians mistakenly believed it was not an opioid narcotic for years due to it not being controlled but also because they never read the literature on the drug including the package insert that clearly stated it was a mu receptor agonist (opioid narcotic) in the second paragraph of the package insert. Therefore many physicians prescribed it freely for pain believing it to have no addictive properties. The drug is a mu opioid pro-drug, meaning the metabolite is from 100 to 800 times as potent as an effect on the opioid receptor. Ultram also inhibits the reuptake of both serotonin and norepinephrine. Blocking the opioid receptor with naloxone does not block all the analgesic effects of the drug demonstrating part of the analgesic effect is due to the reuptake inhibition of serotonin and norepinephrine. One of the most concerning side effects of tramadol is the development of seizures, especially if taking antidepressants while using higher dosages of tramadol, and particularly more severe when taking tricyclic antidepressants such as amitriptyline (Elavil) or cyclobenzaprine (Flexeril) that is also a tricyclic antidepressant being marketed as a muscle relaxant. Tramadol has a relatively low addiction potential. Overdose deaths have been reported rarely when taken by itself, but several times with alcohol or benzodiazepines in combination.
It is considered to be 10% of the potency of morphine.
Loperamine- Lomotil, is being used to try to obtain enough of the drug to avoid opioid withdrawal. Immodium is another preparation being used for the same purpose. These drugs are anti-diarrhea drugs sold in grocery stores. Taking more than 4 of these a day can lead to cardiac arrhythmias and death.
Butorphanol-Stadol nasal spray is sometimes used by addicts but the drug can reverse some of the euphoria of the other opioids, and is very expensive since many use 4-6 bottles a day. It is rarely used any more in the US.
Nalbuphine- Nubain, is approximately 1/3 as potent as morphine and is a synthetic opioid. It is only available as an injectable form, and given to a person that already has another opioid on board, it can reverse the effect of the other opioid, precipitating fulminant withdrawal. It is only uncommonly used in the hospitals now.
Injectables: Sufentanil, Remifentanil, Alfentanil: These are primarily used in hospitals. Sufentanil (Sufenta) is approximately 800 times as potent as morphine and lasts several hours. Remifentanil is an injectable drug lasting only a few minutes whereas alfentanil (Alfenta) lasts for a few hours.
W-Series Opioids- This is a series of 32 synthetic drugs discovered in the 1980s at the University of Alberta, some of which have tremendous potency. For instance W-18 is 100 times as potent as fentanyl or 8000 times as potent as morphine. Nefarious drug dealers will lace heroin with W-18 causing instant death from respiratory depression.
Levorphanol- This drug has been used for cancer and non-cancer pain for decades, but limited production of the drug has caused it to be available only intermittently, therefore it is rarely used (or obtainable). It was an intermittent activity drug similar to methadone (6 hour activity)
LAAM- Is a FDA approved alternative to methadone, but has been effectively removed from the market due to side effects.
Others- There are hundreds of opioids in many different classes, but almost all are not approved for use by the FDA and DEA in the US. A few are used in other countries but not in the US. Chemists sometimes make these drugs illegally to be sold in the US, however with there being so many others available, it would be difficult to convince people to use something completely foreign to them, and therefore they generally are not available in the US.