TABLE OF CONTENTS
Title Page – – – – – – – – – i
Certification – – – – – – – – – ii
Dedication – – – – – – – – – iii
Acknowledgements – – – – – – – – iv
Table of Content – – – – – – – – – vi
List of Table – – – – – – – – – viii
List of Figure – – – – – – – – ix
List of appendices – – – – – – – – – x
Abstract – – – – – – – – – xii
CHAPTER ONE: INTRODUCTION
1.1 Background of the Study – – – – – – 1
1.2 Statement of the Problems – – – – – – 10
1.3 Purpose of the Study – – – – – – 11
1.4 Significance of the Study – – – – – – 12
CHAPTER TWO: LITERATURE REVIEW
2.1 Theoretical Framework – – – – – – 14
2.2 Empirical Review – – – – – – – 21
2.3 Hypotheses – – – – – – – – 26
2.4 Operational Definition of Terms – – – – – – 27
CHAPTER THREE: METHOD
3.1 Design – – – – – – – 29
3.2 Participants – – – – – – – 29
3.3 Instruments – – – – – – – 30
3.4 Procedures – – – – – – 32
3.5 Statistical Analysis – – – – – – 43
CHAPTER FOUR: RESULTS
4.1 Observations – – – – – – – 44
CHAPTER FIVE: DISCUSSION, CONCLUSION AND RECOMMENDATIONS
5.1 Discussion of Findings – – – – – 61
5.2 Conclusion – – – – – – 66
5.3 Implications of the Study – – – – – 67
5.4 Recommendations – – – – – – 68
5.5 Limitations of the Study – – – – – 69
REFERENCES – – – – – – 70
Appendix – – – – – – – – 77
In this study, opioid induced psychological withdrawal syndromes in albino rats were investigated. Tramadol was typically used in this study. 9 adult albino rats were divided into 2 experimental groups and 1 control group. After 14days of acclimatization, varying dosage of tramadol hydrochloride tablets was administered to the experimental rats orally following the body weights. Such parameters as aggression, anxiety, appetite loss, sleeping problems, irritation, depression, restlessness and drug cravings in the rats were observed and recorded. One – way analysis of variance was used to determine whether significant difference exist in the experimental rats behaviour in terms of reduction in sleeping hours, period of social interaction (depression),and average daily feed intake (appetite loss) as compared to that of the control group rats. The result showed that there was significant difference in all the three behaviours. Also, all the parameters were seen to be associated with tramadol withdrawal. In conclusion, tramadol hydrochloride tablet when taken orally for a prolonged period of time has the potency to caused withdrawal symptoms such as aggression, irritation, anxiety, appetite loss, depression, restlessness, poor sleeping behaviours and intent drug cravings as observed in this study.
1.1 Background to the Study
Individuals who are in the early stages of recovery typical experience two types of withdrawal; acute withdrawal (physical) and post-acute withdrawal (psychological). During active addiction, the brain becomes conditioned to rely on substances for certain chemical processes, which affects how we think and feel. Once the individual stops using a substance, the mind must readjust back into a normal homeostasis (Recovery.org., 2019).
Many drugs superficially increase the production of dopamine, the neurotransmitter responsible for feelings of reward and pleasure. Once someone stops using a substance that affect dopamine levels, the brain must relearn how to produce dopamine naturally. This can take time, and the individual may experience psychological withdrawal. For many, overcoming this psychological withdrawal can be the most difficult challenge in recovery.(Recovery.org., 2019).
Unlike physical withdrawal symptoms, which typically last three days to a week psychological withdrawal symptoms may linger for up to two years. Despite the potentially long-tasting symptoms of psychological withdrawal, it is important to know that the severity of these symptoms dramatically diminishes over time. This is especially true for those who receive proper aftercare treatment (Recovery.org., 2019).
Withdrawal syndrome (also called a discontinuation syndrome) is a set of symptoms (both physical and psychological) occurring in discontinuation or dosage reduction of some types of medications and recreational drugs. The risk of a discontinuation syndrome occurring increases with dosage and length of use (Wikipedia.org., 2017). Psychological effects that occurs when a person cease to use a chemical and/or addictive substance.
- Such as some prescription medications, illegal drugs, alcohol or nicotine. It can also occur when someone quits a habit such as compulsive shopping or gambling (addictive behaviours) (Goodtherapy. Org., 2015).
Some symptoms of psychological withdrawal include; depression, extreme irritability, anxiety, agitation, weepiness and restlessness, sleeping problems, difficulty concentrating or engaging in everyday tasks, sensitively to stress; lack of motivation, grieving the loss of the addiction, rapid mood change, and feeling of being unfulfilled(Goodtherapy.org., 2015).
For many, this mental form of withdrawal can be a roller coaster that is filled with varying degrees of the above symptoms. Unfortunately, the inability to recognize and cope with psychological withdrawal symptoms is often the catalyst for relapse (Recovery.org., 2019).
In order for symptoms of withdrawal to occur, one must have first developed a form of drug dependence. This may occur as physical or psychological dependence or both. Drug dependence develops from consuming one or more substances over a period of time. Dependence arises in a dose dependent manner and produces withdrawal symptoms that vary with the type of drug that is consumed. For example; prolonged use of an anti-depressant medication is likely to cause a much different reaction when discontinued compared to discontinuation of an opioid such as heroin.
Opioids are natural or synthetic (made in laboratories to mimic the properties of natural opioids) chemicals that interact with opioid receptors on the nerve cells in the body and brain and reduce feelings of pain. They are a class of drugs that include prescription pain relievers, synthetic opioids and heroin. Prescription opioids are meant to be used to treat acute pain (such as recovering from injury or post-surgery), chronic pain, active-phase cancer treatment, palliative and end-of-life care. Many people rely on prescription opioids to help manage the conditions under the care of a physician (CDC, 2018).
Opioids reduce the perception of pain, but can also cause drowsiness, mental confusion, euphoria, nausea and constipation. At high doses, they can depress respiration. Prescription pain relievers include oxycodone (oxycotin(R)), hydrocodone (vicodin(R)), codeine, morphine and others. Synthetic opioids include fentanyl, methadone, pethidine, tramadol, and carfentanil.
In this project work, the specific opioid that was used is Tramadol. Tramadol is an opioid pain medication used to treat, moderate to moderately severe pain (TASHP, 2014). When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour (TASHP, 2014). It is also available by injection (BMA, 2017). It may be sold in combination with paracetamol (acetaminophen) or as longer-acting formulation (TASHP, 2014; BMA, 2017).
Tramadol is marketed under a variety of trade names such as Ultram, ultracet, zytram and others (drug.com, 2018). Tramadol is most often prescribed to treat moderate levels of pain including dental, osteoporosis, and neuropathy in both acute and chronic settings. It is also approved for treating cancer pain in periods less than 3 months (TASHP, 2014). Common side effects of tramadol include; constipation, itchiness, and nausea (TASHP, 2014). Serious side effects may include; seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction (TASHP, 2014). Tramadol is contraindicated with people deficient in CYP2D6 enzymes (TGA eBusiness Services, 2014). The enzymes are crucial to the therapeutic effects of tramadol by means of enabling tramadol’s metabolism to desmetramadol (Rossi, 2013). A change in dosage may be recommended in those with kidney or liver problems (TASHP, 2014). It is not recommended in those who are at risk of suicide or in those who are pregnant (TASHP, 2014; BMA, 2017). While not recommended in women who are breastfeeding, those who take a single dose should not generally stop breast feeding (Drug.com; 2016).
Tramadol acts by binding to m-Opioid receptors on neurons (TASHP, 2014, Leppert, 2009). It is also a serotonin-norepinephrine reuptake inhibitor (SNRI) (TASHP, 2014, Leppert, 2009). It is converted in the liver to O-desmethyltramadol, and with stronger binding to the m-Opioid receptor (Raffa et al; 2012).
Tramadol was patented in 1963 and launched under the name “Tramal” in 1977 by the West German pharmaceutical company Grunenthal GmbH (Leppert, 2009; Fischer et al, 2006). In the mid-1990s, it was approved in the United Kingdom and United States (Leppert, 2009). It is available as a generic medication and marketed under many brand names with Ultram and ultracet being the most prescribed and recognized worldwide (TASHP, 2014; Drug.com, 2018). In 2016, it was the 39th most prescribed medication in the United States, with more than 19 million prescriptions (Clinical C.com; 2018).
Compared to other drugs and medications, tramadol is relatively young. It stands apart from other opiates in that it is a fully synthetic drug, which means that it is man-made and does not occur in nature. This is in contrast to morphine and codeine-which are natural opiates derived from the opium poppy. It also differs from drugs like hydromorphone, hydrocodone, and oxycodone which, while also semi-synthetic and made in a laboratory, still retrain some natural qualities.
Again, tramadol has an uncommon dual-acting benefit. It works as an opiate in the expected way to manage the perception of pain, but beyond that, it allows increased availability of two other neurotransmitter chemicals in the brain called norepinephrine and serotonin. Norepinephrine is noted for its ability to improve concentration, and serotonin manages an array of functions including sleep and mood.
Tramadol is used primarily to treat mild to severe pain, both acute and chronic (Rossi S., 2013; Grond & Sablotzki, 2004). Its analgesic effects take about one hour to come into effect and 2 to 4 hours to peak after oral administration with an immediate-release formulation (Grond & Sablotzki, 2004; Rossi S., 2013). On a dose-by dose basis, tramadol has about one-tenth the potency of morphine and is practically equally potent when compared with pethidine and codeine (Lee et al, 1993). The painkilling effects of tramadol last for about 6 hours (Ground & Sablotzki, 2004). Also, fair evidence was found for tramadol as a second-line treatment for fibromyalgia (MacLean & Schwartz, 2015).
Tramadol is available in various dosage forms such as liquids, syrups, drops, elixirs, effervescent tablets and powders for mixing with water capsules, tablets including extended-release formulations, suppositories, compounding powder and injections (Rossi, 2013).
The most common adverse effect of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain vertigo, vomiting, constipation, drowsiness, and headache (Langhey et al., 2010; Keating, 2006). Compared to other opioids, respiratory depression and constipation are considered less of a problem with tramadol (Keating, 2006).
Chronic tramadol administration may include a strategy of immune tolerance (Bryant et al; 1988), although in contrast to typical opioids, it may enhance immune function (Sacerdote et al., 2000; Liu et al., 2006).
Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome. (Prescrire et al., 2003). These include both symptoms typical of opioids withdrawal and those associated with serotonin-norepinephrine reuptake inhibitor withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus (Epstein et al., 2006). Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attack, and confusion (Senay et al., 2003). In most cases, tramadol withdrawal will set in 12-20 hours after the last dose, but this can vary (Epstein et al., 2006). Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogues (Epstein et al., 2006). Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous (Jovanovic-Cupic et al., 2006).
Recognized risk factors for tramadol overdose include depression, addiction, and seizures (Randall & Crane, 2014). Deaths with tramadol overdose have been reported and are increasing in frequency in Nigeria, the majority of these overdoses involves other drugs including alcohol (Randall & Crane, 2014).
1.2 Statement of the Problems
In 2017, more than 70,200 Americans died from drug overdoses, including illicit drugs and prescription opioids, a 2- fold increase in a decade (CDC). The United nations Office on Drugs and Crime (UNODC) reported that about 14.4% or 14.3 million people aged 15 and 64 years used drug in 2018. Out of these, 4.6 million people used pharmaceutical opioids such as tramadol, codeine or morphine while about 87.000 people used heroin. The report also had it that, I in every 5 users is dependent, and 1 in 5 people suffered drug use disorders.
Also, UNODC in their annual World Drug Report (2018) found that opioids use increase in Africa, Asia, Europe and North America and that of the 585,000 people who died across the globe in 2017 as a result of drug use, two-thirds of those cases were as a result of opioids use. The report also had it that the use of tramadol was of great concern in Nigeria. Tramadol use was second only to marijuana.
On 4 April 2019, the Nation Newspaper reported that 3 students of the Federal University of Technology (FUTO) Owerri died after taking a mixture of tramadol codeine and vodka, while one student was unconscious. Daily post published on May 3, 2018 reported of a 20 year old man who died of tramadol overdose (over a 1000mg) in Otukpo, Benue State, Nigeria.
Many literature on drug withdrawal tend to consider the physiological (physical) withdrawal symptoms more than the psychological aspect, although these two are not very distinct from each other, hence this project work places more emphasis on the psychological distresses a person undergoes when suffering from opioids withdrawal.
1.3 Purpose of the Study
This project work aims at examining and providing literature material on psychological withdrawal syndrome induced by opioids particularly tramadol in the following ways:
- The severity of psychological withdrawal syndrome caused by tramadol discontinuation on users of tramadol.
- To investigate the potency of tramadol with regards to the time frame of forming an addiction / physical dependence in which discontinuation could result in withdrawal syndrome.
1.4 Significance of the Study
This study is expected to inspire and encourage further researches on opioids both prescription opioids, the elicit opioids like heroin and synthetic opioids and attract criticisms to help the researcher learns more.
To the physicians the world over this project will create awareness on the danger of opioids as many abusers of opioids started it use as medication for either acute or chronic pain or as cough medicine. Thus the physician will learn to think of other medications to serve those purposes rather than opioids and only consider it as the last option in the absence of any other medication to relieve the individuals.
To the National drug Law Enforcement Agency (NDLEA), this project will serve as a tool for making law regarding the sales and distribution of opioids as prescription only drugs rather than over-the-counter (OTC) drugs.
To the general Nigerian Public who may have taken advantage of the fact that tramadol or other opioids were prescribed to him/her by a doctor and then went ahead to abuse it as most literature reveals it to the researcher, this study is to remind you that you are doing yourself more harm than good and a firm advice to strict adherence to pharmacological prescription if need arise rather than advantage taking.