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 Table of Contents  
CASE SERIES
Year : 2021  |  Volume : 22  |  Issue : 1  |  Page : 80-83

Effectiveness of buprenorphine in detoxification and naltrexone in relapse prevention of tramadol-dependent patients: A case series


Additional Professor, Department of Psychiatry, AIIMS, Mangalagiri, Andhra Pradesh, India

Date of Submission27-Mar-2021
Date of Acceptance20-Apr-2021
Date of Web Publication01-Jun-2021

Correspondence Address:
Dr. Vijaya Chandra Reddy Avula
Department of Psychiatry, AIIMS, Mangalagiri, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/amh.amh_39_21

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  Abstract 


Tramadol hydrochloride is a centrally acting synthetic analgesic drug. Its analgesic properties are weak agonist at mu- and kappa-opioid receptors, blockade of reuptake serotonin (5-HT), and norepinephrine at synaptic cleft inhibiting pain transmission. This case series is about the treatment of nine patients who were dependent on tramadol. All patients satisfied criteria for opioid dependency International Classification of Diseases, 10th Revision diagnostic criteria. WHO treatment guidelines for opioid detoxification using Buprenorphine and relapse prevention using oral naltrexone were followed. Detoxification with buprenorphine did not alleviate all withdrawal symptoms. Craving toward tramadol and the cost of naltrexone was a reason to relapse in patients. Cost and failure to address craving lead to noncompliance with naltrexone. Partial agonists like buprenorphine and long-acting agonist like methadone should be used to detoxify and prevent relapse in patients dependent on tramadol.

Keywords: Buprenorphine, electronic prescription, naltrexone, opioid dependence, relapse prevention, tramadol


How to cite this article:
Avula VC. Effectiveness of buprenorphine in detoxification and naltrexone in relapse prevention of tramadol-dependent patients: A case series. Arch Ment Health 2021;22:80-3

How to cite this URL:
Avula VC. Effectiveness of buprenorphine in detoxification and naltrexone in relapse prevention of tramadol-dependent patients: A case series. Arch Ment Health [serial online] 2021 [cited 2021 Jun 19];22:80-3. Available from: https://www.amhonline.org/text.asp?2021/22/1/80/317420




  Introduction Top


Tramadol is a centrally acting synthetic analgesic. It acts as a weak agonist at the mu and kappa receptors and inhibits norepinephrine and serotonin reuptake. M1 is a more active metabolite of tramadol. Inhibition of reuptake norepinephrine and serotonin inhibits pain transmission pathways in the spinal cord. Animal and human research studies on tramadol dependence have shown mixed data. Some studies have been strongly suggestive of dependence and abuse liability, while others indicate low dependence and abuse liability. Animal studies have also been inconclusive; one study on mice showed no tolerance[1],[2] and physical dependence and another study in rats where tramadol produced conditional place preference.[3],[4] Postmarketing surveillance in the USA showed low abuse liability, and those abusing tramadol often use other substances.[5] A study-based Swedish Drug Information System (Swedish) reported abuse of prescribed tramadol in doses of 50–4000 mg/day. Many cases were severe and needed hospitalization for detoxification to treat the discontinuation of tramadol.[6]

Sarkar et al. reported a case series of tramadol dependence in patients' previous history of substance use.[7] Doctors should be cautious in prescribing tramadol and treatment difficulties with high dropout rates from India. In an epidemiological study focusing on opioids in India (Punjab), tramadol was the second most abused after heroin.[8] A bibliometric analysis of research articles on Tramadol showed 2059 research articles published , and 370 reports among them were about Tramadol dependence.[9] From the above, we can draw a fair conclusion that abuse and addiction to tramadol exist. Physicians often prescribe it for treating pain as an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) or other opioids because of its better side effect profile or less addiction potential, respectively. Often, friends of patients suggest the usage of Tramadol to patients to relieve pain, fatigue, and a feel of pleasure.[10] Our case series study predominantly focused on treating withdrawal symptoms with the sublingual buprenorphine and naloxone fixed-dose combination tablet. After detoxification, oral naltrexone 50 mg, a pure antagonist, was used to prevent relapse. We study compliance in using naltrexone and factors affecting compliance.


  Methodology Top


Patient information

We report a case series of nine patients using high doses of tramadol; out of these, five patients attended to the department directly, and other departments referred four patients. All patients satisfied the criteria for substance dependence as per the International Classification of Diseases, 10th Revision (World Health Organization [WHO], 1993),[11] and we admitted them to the psychiatry ward after voluntary written consent. We administered Clinical opiate withdrawal scale(COWS) to measure severity of withdrawal in patients. COWS is an 11-item questionnaire, of which 1 question is purely subjective, 4 questions are subjective and objective, and 6 questions are objective responses scored by a clinician. COWS items had good reliability with Cronbach's alpha 0.78.[12] The Substance Dependence Severity Scale (SDS) has been used to measure dependence severity to various substances, the scale emphasises on psychological dependence towards substances. SDS has good discriminative power and test–retest validity.[13]

Initially, on admission, patients were not given any drugs till the completion of 6 h or appearance of withdrawal symptoms.[14] Patients have been administered with buprenorphine–naloxone 2 mg/0.5 mg sublingual tablet. To address insomnia, lorazepam tablet was used. The WHO dose recommendation of buprenorphine–naloxone (Bup–Nal) has been used to treat withdrawal symptoms (citation). In patients who did not adequate relief of withdrawal symptoms such as restlessness, irritability, and insomnia and pain symptoms with Bup–Nal, we administered lorazepam and NSAIDs or paracetamol, respectively. After a 5-day buprenorphine-naloxone decremental dose regime, a 2-day Bup–Nal free period was allowed before the naloxone challenge test was done. If the patient had no opioid withdrawal symptoms on the naloxone challenge test, he/she has been started on 12.5 mg oral naltrexone, and gradually increased the dose to 50 mg/day. Patients were discharged on 50 mg of naltrexone to be administered under supervision by their relatives.


  Results Top


[Table 1] consists of the details of age of onset of usage, route of usage, usage duration, maximum dose, SDS scores, COWS scores at admission and at initiation of naloxone challenge test, duration of treatment, and relapse and reasons for relapse. Our case series, patients' age ranged between 18 and 35, using tramadol in the dose of 400–2400 mg/day, using tramadol in oral (50 mg) and parenteral route (25 mg/ml 2 ml formulation). Due to small sample size of nine patients, only raw data are presented without any statistical analysis. Clinicians administered COWS to patients after six to eight hours after admission to assess the baseline withdrawal scores. All patients reported high scores in the range of three to five on anxiety, restlessness, and bone or joint or diffuse muscle aches of COWS. Patients score ranged between 1 and 3 on items of sweating, tremor, and gastrointestinal (GI) upset. On clinical examination items of resting pulse rate, yawning, pupil size, and piloerection, all patients scored zero.
Table 1: Patient history, examination, treatment, and relapse details

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All patients required NSAIDs for pain and lorazepam for sleep disturbances. Lorazepam in dose range 4–8 mg/day was initially needed, which during the course was tapered to 2 mg/day. Patients did not develop medical complications requiring of use medication other than those mentioned.

Patients underwent a standard naloxone challenge test. A clinician administered a COWS. Just before, immediately, and 30 min after administration, all patients reported did not show any naloxone-induced withdrawal symptoms and were started on 12.5 mg naltrexone. Over 4 days, it was increased to 50 mg. Patients' stay in the ward for treatment ranged from 15 days to 32 days. Patients at discharged with advice to attendants compulsorily supervise the administration oral naltrexone 50 mg as soon as they wake up in the morning and paracetamol 500 mg if a patient complains of pain and lorazepam 2 mg at nighttime for any difficulty in asleep. Patients in case series were regularly followed up to evaluate identify and treat remnant withdrawal symptoms, compliance towards usage of naltrexone and relapse in usage of Tramadol.

Cases A, B, E, and G relapsed to the use of tramadol in a period of fewer than 6 months based on the history provided by family members. Case A often visited outstation without intimation to avoid naltrexone and to take tramadol. Case B often resorted to hiding the tablet buccally and later spit (as narrated by the patient) and daily consume tramadol. Family members of Case F and Case G reported that naltrexone was very costly and challenging to afford; when they could not procure the tablet, their patients often used tramadol.

Cases C, D, and F by the time of preparing this manuscript for publishing were in follow-up for 16, 11, and 7 months, respectively. These patients were using naltrexone regularly and did not relapse.


  Discussion Top


Tramadol has been an excellent alternative to opioids controlling pain in acute and chronic conditions and has dependence properties as opioids. The severity of the dependence is less severe than classic mu agonists such as heroin, codeine, and morphine (AbdelWahab et al., 2018). Patients dependent on tramadol had opioid withdrawal symptoms such as anxiety, restlessness, and bone and muscle aches. Objective symptoms such as pupil size, yawing, goose flesh, resting pulse rate, sweating, tremor, and GI upset were often absent.[15] The presence of subjective symptoms indicates psychological dependence and less physical dependence (Epstein et al., 2006).[16] Supervised treatment with naltrexone is necessary to prevent relapse; patients often skip naltrexone in preference to tramadol. Oral naltrexone costs around 60–70 INR. Government initiative to make it affordable will increase the compliance to it. Introduction of once a month Food and Drug Administration -approved vitriol intramuscular formulation naltrexone in India would increase the compliance and treatment results.[17] Although the Government of India has classified tramadol as a scheduled H1 drug, ground-level implementation of rules at the pharmacy level is not adequate due to lack of awareness, responsibility, and complacency (due to excess of paperwork) on drug dependence potential of tramadol. An electronic prescription uploaded on a central database that the pharmacy can use will help prevent duplicate issue of medications.[18] Physicians prescribing Tramadol, at dose 200mg/day or more to patients should monitor them for any abuse. They should taper the dose slowly. The key informants' doctors, nurses, and pharmacists should be encouraged to report tramadol abuse instances. Central registries monitoring the production, sales, and collecting information about any abnormal increase in production should be established. Buprenorphine and naloxone combination is a better alternative to antagonist therapy with lesser rates of failure.[19]


  Conclusion Top


Patients who use tramadol at high doses develop dependence. Symptoms of tramadol withdrawal mimic that of opioid withdrawal. Subjective symptoms such as bone pain, muscle aches, and restlessness are more severe than subjective and objective symptoms such as sweating, resting pulse rate, GI upset, tremor, and yawning. Patients in our case series did not show changes in pupil, piloerection, and heart rate. Buprenorphine–naloxone, although alleviated most of the withdrawal symptoms: muscle aches, restlessness, and insomnia, required the addition of NSAIDs and lorazepam, respectively. Even after prolonged abstinence (more than 6 months), patients complained of muscle aches and restlessness. Patients dependent on tramadol required long-term usage of lorazepam to address restlessness. Family members should administer oral naltrexone under strict supervision for better compliance.

Limitations

The cases presented in case series do not have specific inclusion and exclusion criteria. The subjective bias of the author influences assessment of the patient and treatment effects reported. The small sample size of the case series does not permit statistical analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Miranda HF, Pinardi G. Antinociception, tolerance, and physical dependence comparison between morphine and tramadol. Pharmacol Biochem Behav. 1998;61:357-60.  Back to cited text no. 1
    
2.
Zhang M, Jing L, Liu Q, Wen RT, Li JX, Li YL, et al. Tramadol induces conditioned place preference in rats: interactions with morphine and buprenorphine. Neurosci Lett. 2012;520:87-91.  Back to cited text no. 2
    
3.
Ren YH, Zheng JW. Influence of tramadol on morphine discriminative behavior in rats. Acta Pharmacol Sin. 2000;21:924-6.  Back to cited text no. 3
    
4.
Sprague JE, Leifheit M, Selken J, Milks MM, Kinder DH, Nichols DE. In vivo microdialysis and conditioned place preference studies in rats are consistent with abuse potential of tramadol. Synapse. 2002;43:118-21.  Back to cited text no. 4
    
5.
Cicero TJ, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend. 1999;57:7-22.  Back to cited text no. 5
    
6.
Tjaderborn M, Jonsson AK, Ahlner J, Hagg S. Tramadol dependence: a survey of spontaneously reported cases in Sweden. Pharmacoepidemiol Drug Saf. 2009;18:1192-8.  Back to cited text no. 6
    
7.
Sarkar S, Nebhinani N, Singh SM, Mattoo SK, Basu D. Tramadol dependence: a case series from India. Indian J Psychol Med. 2012;34:283–5.  Back to cited text no. 7
    
8.
Avasthi A, Basu D, Subodh BN, Gupta PK, Goyal BL, Sidhu BS, et al. Epidemiology of dependence on illicit substances, with a special focus on opioid dependence, in the State of Punjab, India: Results from two different yet complementary survey methods. Asian J Psychiatr. 2019;39:70-9.  Back to cited text no. 8
    
9.
Sweileh WM, Shraim NY, Zyoud SH, Al-Jabi SW. Worldwide research productivity on tramadol: a bibliometric analysis. Springerplus. 2016;5:1108.  Back to cited text no. 9
    
10.
Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the clinical opiate withdrawal scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend 2009;105:154-9.  Back to cited text no. 10
    
11.
World Health Organization. The ICD-10 classification of mental and behavioural disorders : diagnostic criteria for research. CIM-10ICD-10 Classif Int Mal Dixième Révis Chapitre VF Troubl Mentaux Troubl Comport Critères Diagn Pour Rech [Internet]. 1993; Available from: https://apps.who.int/iris/handle/10665/37108. [Last accessed on 2017 Feb 12].  Back to cited text no. 11
    
12.
Tompkins DA, Bigelow GE, Harrison JA, Johnson RE, Fudala PJ, Strain EC. Concurrent validation of the Clinical Opiate Withdrawal Scale (COWS) and single-item indices against the Clinical Institute Narcotic Assessment (CINA) opioid withdrawal instrument. Drug Alcohol Depend. 2009;105:154-9.  Back to cited text no. 12
    
13.
Miele GM, Carpenter KM, Cockerham MS, Trautman KD, Blaine J, Hasin DS. Substance Dependence Severity Scale. Addict Behav. 2001;26:603-12.  Back to cited text no. 13
    
14.
Uchtenhagen A, Rehm j. WHO Guidelines for psychosocially assisted pharmacological treatment of persons dependent on opioids [Internet]. WHO; 2007 Available from: https://www.who.int/substance_abuse/activities/background_paper.pdf [Last accessed on 2021 Dec 03].  Back to cited text no. 14
    
15.
Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, et al. Physical dependence on Ultram® (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend. 2003;69:233–41.  Back to cited text no. 15
    
16.
Epstein DH, Preston KL, Jasinski DR. Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: Lessons from tramadol. Biol Psychol. 2006;73:90–9.  Back to cited text no. 16
    
17.
Kjome KL, Moeller FG. Long-Acting Injectable naltrexone for the Management of patients with Opioid Dependence. Subst Abuse Res Treat. 2011;5:SART.S5452.  Back to cited text no. 17
    
18.
Figge HL, Fox BI, Tribble DA. Electronic prescribing of controlled substances. Am J Health Syst Pharm. 2009;66:1311-6.  Back to cited text no. 18
    
19.
Stotts AL, Dodrill CL, Kosten TR. Opioid dependence treatment: options in pharmacotherapy. Expert Opin Pharmacother. 2009;10:1727-40.  Back to cited text no. 19
    



 
 
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