Tag: tramadol

12/15/20

Tramadol Is not a Safe Opioid

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The 2020 World Drug Report said the non-medical use of opioids has always been associated with the most serious health consequences among the various types of drugs. But in the last few years new threats have emerged with regard to the non-medical use of pharmaceutical opioids, leading to alarming rates of dependence and overdose deaths. The problems in North America with fentanyl and its analogues have led to an unprecedented increase in opioid overdose deaths. But in West, Central and North Africa, the Middle East and Asia, another opioid has emerged as a major concern—tramadol.

Tramadol’s potency was said to be comparable to codeine, about 10% the potency of morphine. This led to initial belief that it had a low risk of abuse when it was brought to market in the 1960s by the German pharmaceutical company Grunenthal. However, researchers later found that tramadol releases a far more powerful dose because of how it is metabolized by the liver. An article in The British Medical Journal, “Chronic use of tramadol after acute pain episode” said tramadol undergoes demethylation in the liver to the active metabolite desmatramadol, giving it an opioid effect comparable to morphine.

The BMJ article reported a study by researchers at the Mayo clinic that found patients who received tramadol for the acute treatment of pain had slightly higher rates of long-term opioid use after surgery. The senior author of the study said their finding did not support the idea that tramadol is less habit forming than other opioids. The lead author of the study said: “And while tramadol may still be an acceptable option for some patients, our data suggests we should be as cautious with tramadol as we are with other short-acting opioids.” Tramadol use has been increasing and was the third most prescribed opioid in the study at 4%, after hydrocodone (51%) and oxycodone (38%). “Although all factors related to the safety of a drug must be considered, from the standpoint of opioid dependence, the Drug Enforcement Administration and FDA should consider rescheduling tramadol to a level that better reflects its risks of prolonged use.”

While many countries in West, Central and North Africa report the non-medical use of tramadol as one of the main threats in drug use, quantitative information on the actual size of the population using tramadol non-medically was not available in most countries, according to the 2020 World Drug Report. However, treatment data in West African countries revealed tramadol to be the main drug of concern for people with drug use disorders. “Tramadol ranks highly among the substances for which people were treated in West Africa in the period 2014–2017.” In North Africa, Egypt reported tramadol is the main opioid used non-medically. In drug treatment, tramadol was also the primary drug, accounting for 68% of all people treated for drug use disorders in 2017. In the Sudan, the increasing non-medical use of pharmaceutical drugs among young people includes: tramadol, benzodiazepines, cough syrups and antihistamines, trihexyphenidyl (an antiparkinsonian agent), anticonvulsants, pregabalin and gabapentin.

In Iran, a recent study estimated that or 200,000 people aged 15-49 in urban centers had misused tramadol, most of whom were young people. The past 12-month of non-medical use of tramadol in the general population was 4.9 percent among men and .5 percent among women. In recent years, tramadol intoxication and fatal overdose, especially among young people with a history of substance use disorder and psychiatric comorbidity, has been a major cause of emergency department admissions. Among these cases, tramadol has been misused with other substances, especially benzodiazepines. “Tramadol was also found to be the cause of death in around 6 per cent of the total drug overdose death cases in the Islamic Republic of Iran reported in different studies from 2006 to 2017.”

AP News reported in “How tramadol, touted as safer opioid, became 3rd world peril,” that mass abuse of tramadol spans continents from India to Africa and the Middle East, creating international havoc. Some experts blame a loophole in narcotics regulation and a miscalculation of the drug’s danger. It was touted as a way to relieve pain with little risk of abuse. Unburdened by international controls that track most dangerous drugs, tramadol flows freely around the world. “But abuse is now so rampant, that some countries are asking international authorities to intervene.”

Grunenthal is campaigning to keep the status quo with tramadol regulation, arguing that typically it is illicit counterfeit pills causing problems. International regulations make narcotics difficult to get in countries with disorganized health systems. Adding tramadol to the list, the company said, would deprive suffering patients access to any opioid at all. The secretary of the World Health Organization’s committee recommending how drugs should be regulated said this is a huge public health dilemma. “It’s a really very complicated balance to strike.” Tramadol is available in war zones and impoverished nations because it is unregulated—the same exact reason it is widely abused.

Tramadol has not been as deadly as other opioids, and the crisis isn’t killing with the ferocity of America’s struggle with the drugs. Still, individual governments from the U.S. to Egypt to Ukraine have realized the drug’s dangers are greater than was believed and have worked to rein in the tramadol trade. The north Indian state of Punjab, the center of India’s opioid epidemic, was the latest to crack down. The pills were everywhere, as legitimate medication sold in pharmacies, but also illicit counterfeits hawked by street vendors.

Authorities in Punjab seized hundreds of thousands of tablets, banned most pharmacy sales and shut down pill factories, pushing the price from 35 cents for a 10-pack to $14. When the government opened a network of treatment centers, fearful those who had become addicted would resort to heroin out of desperation, hordes of people rushed in seeking help. Tramadol had become as essential as food. A 30-year-old auto shop welder said, “Like if you don’t eat, you start to feel hungry. Similar is the case with not taking it.”

In 2016, Jeffery Bawa, an officer with the UN Office on Drugs and Crime, traveled to Mali in West Africa, one of the world’s poorest countries, which also struggles with civil war and terrorism. When he asked people what their most pressing concern was most said tramadol, not hunger or violence. At a United Nations meeting on tramadol trafficking, Nigerian officials said the number of people living with addiction is far higher now then the number with AIDS or HIV. In Cameroon, scientists thought they had discovered a natural version of tramadol in tree roots. “But it was not natural at all: Farmers bought pills and fed them to their cattle to ward off the effects of debilitating heat. Their waste contaminated the soil, and the chemical seeped into the trees.”

Police began finding tramadol pills on terrorists. It seems they now traffic tramadol to fund their networks and use it to bolster their own violent behavior. Most of the supply was coming from India, where pill factories produced counterfeits and shipped them in bulk around the world, “in doses far exceeding medical limits.” In 2017, law enforcement reported confiscating $75 million worth of tramadol from India on route to the Islamic State. Another 600,000 tablets headed for Boko Haram were intercepted. Three million more tramadol tablets were found in a pickup truck in Niger, in boxes disguised with U.N. logos.

Grunenthal has persisted with its campaign to keep tramadol unregulated. It funded surveys that found regulation would impede pain treatment and even paid consultants to travel to the WHO to make their case that tramadol is safer than other opioids. But that could change. Referring to the above-described Mayo Clinic study, AP News noted the researchers were surprised when they found their data indicated patients prescribed tramadol were just as likely to move on to long-term use as other opioids. The lead researcher of the Mayo study said: “There is no safe opioid. Tramadol is not a safe alternative. It’s a mistake that we didn’t figure it out sooner. It’s unfortunate that it took us this long.”

08/27/19

Global Troubles with Tramadol

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In the US, we see synthetic opioids like fentanyl grabbing headlines, and rightly so. The CDC reported the number of drug overdose deaths involving fentanyl increased from 1,663 in 2011 to 18,335 in 2016. The death rate more than doubled between 2013 and 2014, nearly doubled from 2014 to 2015 and more than doubled again from 2015 to 2016. Yet the World Drug Report 2019 said the non-medical use of tramadol required equally urgent attention, particularly in Africa. Global seizures of tramadol increased from 9 tons in 2013 to a record high of 125 tons in 2017. The largest quantity of tramadol seized from 2013 to 2017 was 96 tons by Nigeria, followed by Egypt with 12 tons. The main destinations were countries in West and Central Africa.

The fact that tramadol has been intercepted in areas close to where the Islamic State and some of its associated groups have been active has led to speculation that tramadol trafficking may be used to finance terrorist activities and used non-medically by their fighters to suppress pain and increase endurance. The largest tramadol seizures in Europe in recent years concerned shipments ultimately bound for North Africa, but they were modest in comparison to those intercepted by some countries in North Africa and the Middle East. “There have also been reports of non-medical use of tramadol in North America, Europe, East and South-East Asia, and Oceania, where diversion from licit sources has been reported in a number of countries.” See the following map.

Dr. Mahmoud Elhabiby reported the 2015 National Drug Survey in Egypt found that tramadol dependence (2.4%) ranked just behind cannabis (2.5%). “Moreover, the study show that Tramadol is the most prevalent opioid that causes dependence;” higher than heroin (.3%).

In Nigeria a cross sectional study where clients’ medical records were reviewed found the prevalence of tramadol abuse was 54.4% for the stipulated review period. In the original study, 67% of the subjects reported using multiple psychoactive substances, with benzodiazepines (44%) and cannabis (53%) being the most common. “Over 91% of the subjects obtained the drugs without a prescription and over 60% met at least three ICD-10 Diagnostic criteria of dependence.”

The CEO of Ghana’s FDA, Delese Mimi Darko, said “It is important we let people know that abusing medicines like Tramadol can have bad consequences, including death.” There have been reported cases of armed robbery, youth vandalism, car accidents, and in some cases, violence linked to the use of tramadol. The FDA in collaboration with the police seized over 500,000 capsules of tramadol in 2017. Given Ghana’s porous borders, tramadol abuse is a regional problem. Darko called for the development of a national tramadol abuse prevention strategy.

In December of 2017 the United Nations Office on Drugs and Crime (UNODC) warned the international community of the implications of the non-medical use of tramadol on the economies and security of West Africa. The UNODC Regional Representative, Pierre Lapaque, said “The rise of tramadol consumption and trafficking in the region is serious, worrying, and needs to be addressed as soon as possible. We cannot let the situation get any further out of control.” Reportedly tramadol is smuggled through the Gulf of Guinea by transnational organized crime networks, through areas partially controlled by armed groups and terrorist organizations.

By the end of September 2017, over 3 million tablets were seized in Niger, packed in boxes with the United Nations logo. In August of 2017, Cameroonian customs officials on the border of Nigeria seized 600,000 tablets intended for Boko Haram. In August of 2018, the UNODC organized a workshop to address the opioid problem in West Africa. “The event brought together senior representatives of law enforcement and health-care services, justice and law enforcement, as well as chiefs of the Inter-ministerial drug committees from Togo, Nigeria, Niger, Ghana, Benin and Côte d’Ivoire.”

The problem of abusive consumption and trafficking of tramadol plays a direct role in the destabilization of the region, as not only do groups smuggle tramadol across borders to generate revenues, they also use it for themselves. As stated by Mr. Lapaque, “Tramadol is regularly found in the pockets of suspects arrested for terrorism in the Sahel, or who have committed suicidal attacks. This raises the question of who provides the tablets to fighters from Boko Haram and Al Qaeda, including young boys and girls, preparing to commit suicide bombings”.

A study done of patients visiting pharmacies in northern Iran showed that 56% of patients who sought tramadol did not have a prescription. “More than 63% of patients reported a history of addiction or drug abuse.” The majority of people seeking tramadol were adolescents/young adults, under the age of 30. Fifty-five percent were under the age of 18. “More than 71% had been able to get access to tramadol without a prescription in the past.” And more than 71% had taken at least two courses of tramadol for more than a week in the past year.

Another study of Egyptian university students by Bassiony et al, “Opioid Use Disorders Attributed to Tramadol Among Egyptian University Students,” found the prevalence of tramadol use was 12.3% among university students. It was higher among males (20.2%) than females (2.4%). Only 15% were using tramadol alone. One-fifth of these students started with tramadol as their first drug. The average age at onset of tramadol use was 17.6 years of age. There was a considerable relationship between tramadol use and other substances. “Smoking, cannabis, and alcohol use predict tramadol use. About 60% of students who use tramadol had drug-related problems and 30% had dependence.”

A different study by Medhat Bassiony and others, “Adolescent tramadol use and abuse in Egypt,” stated tramadol abuse liability was underestimated and the evidence for abuse and dependence was emerging. Here the prevalence of tramadol use was 8.8% among school students, with the average age of onset of tramadol use was 16.5 years of age. Eighty-three percent reported using tramadol alone and the remaining 17% combined tramadol, alcohol and cannabis. Two-thirds of these students started with tramadol as their first drug after they started smoking tobacco. Over one-third of tramadol users had drug-related problems and 6% had drug dependency concerns. They recommended:

Large population-based longitudinal studies in adolescents and young adults are needed to estimate the prevalence, risk factors and consequences of tramadol use in Egypt. In addition, the possible role of tramadol as a gateway drug in the development of substance abuse and dependence in Egypt should be investigated.

Returning to the global perspective, the World Drug Report 2019 estimated 53 million people used opioids at least once in the past year, of whom half were past-year users of opiates, heroin and opium. The highest prevalence of non-medical use of opioids was in North America, with 4% of the population between 15-66. This represented 25% of global opioid users. The major opioids of concern in North America were hydrocodone, oxycodone, codeine and tramadol. The use of opioids in Australia and New Zealand was much higher (3.3% of the adult population) than the global average (just over 1%), with the non-medical use of opioids also being the main opioids of concern. See the following chart:

While America struggles with its own opioid crisis, across much of Africa and the Middle East tramadol is the drug of choice; a choice “fueled by cut-rate Indian exports and inaction by world narcotics regulators.” Unlike other opiates, tramadol isn’t regulated by the International Narcotics Control Board. So, it flows freely from factories in India and Egypt into Gaza, where the tramadol crisis started in the tunnels. Working grueling 12-hour shifts in the underground tunnel network, tramadol was freely exchanged between tunnel workers. “Bosses handed out pills before shifts to keep people moving amid the stresses and dangers.”

Tramadol was cheap. One pill cost just two shekels (56 cents). One 17-year old working in the tunnels was soon taking 8 pills daily. During the wars with Israel, he kept working. The bosses paid extra if he did, “so he self-medicated with tramadol as the bombs fell.” But then Egypt and Israel began flooding and bombing the tunnels and it was too dangerous to do tunnel work anymore. Now 23, he found himself unemployed and addicted to tramadol. However, the tramadol wasn’t the same quality as when he had started using, so he he needed more.

Doctor Khaled al-Safadi, who has worked in Gaza’s Psychiatric Hospital for 15 years, said: “The percent [of tramadol users] is rising because of the severe situation, the siege that we are in, the generation that has no income. . . It’s an escape from the world they are living in.” Last year he opened the first inpatient ward for treating drug addiction. Of the 12 beds on the ward, just two were filled. “Drug abusers are afraid to seek help because of social stigma and lack of trust in dealing with government institutions—combined with the government’s own inattention to these pressing issues.”

But tramadol keeps coming. Instead of coming through the tunnels, it is smuggled in smaller quantities in washing machines and gas canisters. The collapse of the tunnel trade and high use has pushed prices up. Ten years ago, 20 shekels paid for 10 tramadol pills; today that buys just one. “Even the one escape left to them, getting high, is now increasingly unattainable.”

Don’t believe the myth that tramadol is a non-addictive, non-opioid alternative. It is an opiate agonist, meaning it binds to the mu receptor and activates the receptor to produce a biological response, the same as does heroin. It has a significant potential for overdose or poisoning. In excessive doses, whether alone or in combination with other CNS depressants such as alcohol, it can result in drug-related death.

Tramadol can cause withdrawal symptoms, particularly if it has been used regularly over a long time period or in high doses. Withdrawal symptoms, particularly if you stop using it suddenly, may include restlessness, watering eyes, runny nose, nausea, sweating and muscle aches. Seizures are more likely to occur at the high doses of tramadol abuse. According to drugs.com,

Serious side effects including seizures and serotonin syndrome may also occur due to drug interactions. Examples of drug classes where this might occur include the serotonin reuptake inhibitors (SSRIs, SNRIs), TCAs and MAO inhibitors (like phenelzine or linezolid) — all types of antidepressants. In fact, tramadol should never be used with an MAOI inhibitor or within 14 days of taking an MAOI. Taking tramadol with drugs that already have a seizure risk may worsen that risk.

Tramadol is a Schedule IV Controlled Substance, according to the DEA. It has an abuse potential and as an opiate agonist can cause fatal overdose and respiratory failure. Extended release tablets and capsules have been misused by splitting, breaking, crushing, chewing, snorting or injecting the dissolved products. This results in the uncontrolled delivery of the drug and can result in overdose and death.

A study published in the British Medical Journal sought to examine the risk of prolonged opiate use in patients receiving tramadol versus other short-acting opioids. Receiving tramadol was associated with a “6% increase in the risk of additional opioid use” relative to others receiving other short acting opioids. The researchers concluded people receiving tramadol after surgery had a somewhat higher risk of prolonged opioid use when compared to those receiving other short acting opioids. They suggested federal officials consider reclassifying tramadol and that providers use as much caution when prescribing tramadol as they do with other short acting opioids. For more information on tramadol, see “Trouble with Tramadol.”

05/16/17

Trouble with Tramadol

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Regularly in the U.S. we hear news about the opioid epidemic. There is an ever-growing use of powerful opioids such as fentanyl, which is 50 to 100 times the strength of morphine; and carfentanyl (used as a sedative for large land animals) whose strength is 10,000 times that of morphine. CDC data released on December 30, 2016 indicated that 60.9% of the overdose deaths in 2014 involved an opioid. Between 2014 and 2015 drug overdose deaths increased by: 11.4%.  The CDC suggested this increase was largely driven by synthetic opioids, most likely fentanyl, and heroin. While the opioid epidemic is not uniquely a US problem, it has a different face in other countries, such as Egypt, where the opioid of choice for abusers is tramadol. Yes tramadol, which is one-tenth the potency of morphine.

The Economist said tramadol use in Egypt was everywhere. Taxi drivers used them to stay awake. Wedding guests receive them as token gifts. Petty government officials even accept them as bribes. “Tramadol has become Egypt’s favourite recreational drug, supplanting heroin and cannabis.” Taha, a bank teller, said the drug helps him work. “It just makes you feel relaxed. Even if there are two men fighting to the death beside you, you wouldn’t care.”

There is no social stigma attached to tramadol use. It’s seemingly more religiously acceptable than alcohol or marijuana. Ibrahim began using half a tablet of tramadol because he felt socially awkward at the age of seven. “I found myself feeling unusually outgoing and positive.” Ten years later, he was using ten tablets daily.

Until recently, tramadol sold for the equivalent of 15 to 30 cents per pill. Tramadol use accelerated after the 2011 uprising in Egypt, partly because of the weakened state controls. Ehab El-Kharrat, an Egyptian doctor, said the tramadol came largely from India or China. Customs inspections began to tighten and the price rose sharply. At one point the price reached $1 to $3 a pill. “Since then we have seen a flood of people seeking help.”  The head of a Cairo rehabilitation center said at least 40% of those attending his clinic are addicted to tramadol.

Yet enforcement is poor. Court cases are thrown out because of shoddy police work. Officers are often in cahoots with the drug dealers, or are themselves drug-users. And even if the government succeeds in restricting the supply of tramadol, there may be unintended consequences. If the pills become more expensive, users may switch to stronger heroin. Some worry that the worst of Egypt’s drug problem is yet to come.

The Daily Beast also reported on the tramadol problem in Egypt. A taxi driver threw up the first time he tried tramadol. But now he takes four or five doses daily. He justified his use by saying its one of the few ways to dull the pain of Egypt’s weak economy and trying political circumstances. “Food, gas, everything is so expensive. People are exhausted and take things like tramadol just to keep going.” Young cash strapped males form the core of its users.

A UNODC (United Nations Office on Drug and Crime) official estimated that 90% of the illicit tramadol in Egypt is produced in India, and then smuggled into the country. One supplier said it’s never been easier to keep stocked up on tramadol. Because of its ready availability, its use has begun to spread from younger working class males into the more affluent areas of Cairo, which doesn’t make drug dealers very happy. “It’s not good when [those] people buy tramadol, because it means they won’t buy more expensive things. . . But with the economy and everything, this seems to be what Egyptians want right now.”

The Expert Committee on Drug Dependence of the World Health Organization (WHO) gave an Updated Review Report on tramadol at its thirty-sixth meeting in June of 2014. The report noted how Egypt had up-scheduled tramadol in 2009 because of its increasing rate of abuse. There was also growing evidence of tramadol abuse in other African and West Asian countries, including: Egypt, Gaza, Jordan, Lebanon, Libya, Mauritius, Saudi Arabia and Togo. In most countries it is a prescription-only medicine.

Marketing authorizations for tramadol are held by dozens of companies. The WHO Report listed around thirty-five companies as examples. Corresponding to this, it also goes by dozens of trade names, literally from A (i.e., Acerna, Amanda, or Astradol) to Z (i.e., Zamadol, Zentra, or Zodol). The common formulas in the US are: ConZip, Ryzolt and Ultram.

Overall, tramadol has been seen as having a low potential for drug dependence. However, in the last few years, new data suggests that dependence may occur when it is used daily for more than a few weeks or months. The WHO finding here is consistent with the above reported abuse of Tramadol in Egypt. It is listed as a controlled or scheduled substance in several countries, including: Australia, Iran, Sweden, Venezuela, Ukraine, China, the United Kingdom, Jordan, Saudi Arabia, and Egypt. Since the WHO Report was published, tramadol has become a Schedule IV controlled substance in the U.S.

In summary, the data on the dependence potential of tramadol show that tramadol has a relatively low dependence potential and that dependence is associated with the use of tramadol over an extended period of time (more than a few weeks to months). The data also show a higher risk profile in former drug abusers and in medical staff personnel than in pain patients. Several studies indicate that the incidence of tramadol dependence may differ between countries and within different regions of countries, which may be associated with the availability and prescription practice for tramadol, and with the availability of alternative psychoactive substances for drug abusers.

DrugAbuse.com described tramadol as a fully synthetic opioid originally synthesized by a German company in 1962. It was finally brought to market as Tramal in 1977. It was not until 1995 that it became available in the U.S. as “Ultram.” Initially it was not a controlled substance. By 1996 the FDA revised the product label to require warnings about the potential for abuse. In 2009, the FDA again changed the product warning, now the alert of the possibility of a life-threatening condition, serotonin syndrome.

Between 2005 and 2011, emergency department visits related to non-medical tramadol use rose over 250%. Between 2008 and 2013, prescriptions for tramadol increased by 20 million. In 2014 another increase of 44 million prescriptions of tramadol occurred, possibly a reaction to the rescheduling of Vicodin from Schedule III to Schedule II. Also in 2014, tramadol was made a Schedule IV controlled substances by the DEA.

In 2009, Sansone and Sansone gave a good summary of some of the health risks with tramadol, including a description of serotonin syndrome (SS), and the risk of seizures if it was used concurrently with antidepressants, both tricyclics and SSRIs. There was a “Dear Healthcare Professional” letter distributed by the manufacturer warning of the potential adverse drug event of seizures when using tramadol and antidepressants. A follow up study noted a small and insignificant change in the prescribing habits after the release of the warning letter.

Serotonin syndrome was more common with excessive use/overdose of tramadol or coadministration with other medications, particularly antidepressants among the elderly. SS has been reported with combinations of tramadol and the following: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), fluvoxamine (Luvox), venlafaxine (Effexor), and TCAs (tricyclics). Rimeron was implicated in one case study of tramadol use with elderly residents in a long-term care facility. They summarized their conclusions as follows:

In primary care settings, tramadol is a commonly prescribed synthetic analgesic. Two potential adverse reactions of tramadol are seizures and SS. Either of these reactions may occur with tramadol monotherapy, but both appear to be much more common with either abuse/overdose or in combination with other drugs, particularly antidepressants. These adverse reactions appear to be more common in the elderly. The majority of commonly prescribed antidepressants have been implicated in both of these adverse reactions. Clinicians are advised to be mindful of these potential adverse sequelae when prescribing antidepressants to patients on tramadol, particularly in the elderly and/or those who might be at a heightened risk (i.e., individuals with epilepsy, head injuries, neurological dysfunction). If coadministration is undertaken, we advise careful monitoring for these two particular hazards. Tramadol is a remarkable drug, but like all drugs, effective use entails balancing the benefits versus the risks.

Then on April 20, 2017, the FDA restricted the use of tramadol (and codeine) in children. They also recommended against the use of these medicines in breastfeeding mothers. Tramadol is contraindicated (the FDA’s strongest warning) to treat pain in children younger than 12 years old and for pain in children younger than 18 after surgery to remove tonsils and/or adenoids. “These medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children.”