Clinical and socio-demographic determinants of pentazocine misuse among patients with sickle cell disease, Benin City, Nigeria: a case-control study

Introduction Opioids are a mainstay in sickle cell disease (SCD) pain care. Opioids are known to cause physical and/or psychological dependence. Increasingly, a significant number of Nigerian SCD patients ("Pentaholics") are observed to abuse pentazocine. This trend is associated with new patterns of medical complications. This study aimed to describe the local spectrum of pentazocine abuse complications and identify possible clinical and socio-demographic determinants. Methods We conducted a case control (age matched) study involving 50 booked SCD patients (25 cases and 25 controls) receiving care at the University of Benin Teaching Hospital, Benin City, Nigeria. Relevant clinical and socio-demographic details were collected and analyzed. Associations of categorical variables were tested using chi square or Fishers exact test. Results The median participants’ age and duration of pentazocine abuse/self-use were 32 and 7 years respectively. Pentazocine injections were gotten from local pharmacies and patent medicine stores without any need for physician prescriptions (84% of cases). The buttocks, the thigh and the upper arm/deltoid were the commonest site of injection. Major complications observed were chronic ulcers on the thigh, deep wounds with abscess, healed scar at multiple sites, lower limb swelling and venous thrombosis. Working in healthcare fields/hospitals (Doctor, Nurses, Pharmacists) was significantly associated with pentazocine abuse. Conclusion Health personnel or hospital workers living with SCD are more likely to abuse pentazocine. There is need for prompt triage and optimal control of acute sickle pain, institutional protocols for pain management and strict regulations on supply of prescription drugs such as pentazocine.


Introduction
Sickle cell disease (SCD) is a major public health challenge in Nigeria and many other sub-Sahara African nations [1][2][3]. SCD results from an inherited haemoglobin defect characterized by intra-corpuscular polymerization of haemoglobin molecules, which ultimately deforms the red cell into a crescent (sickle) shape [4,5]. These abnormally shaped red cells undergo accelerated haemolysis, abnormal rheology with micro-vascular occlusion in various organ beds. Phenotypically, affected persons present with numerous complications affecting virtually every organ system. Acute complications include painful crisis, visceral sequestration crisis, hyperhaemolytic crisis, worsening (acute) anaemia, sickle priapism, acute chest syndrome, ischaemic stroke. Long term complications are age related and include sickle cell nephropathy, chronic liver disease, leg ulcers, ophthalmopathy, dilated cardiomyopathy, pulmonary hypertension, immunologic complications, as well psychosocial problems [4,5]. Therefore, the goal of treatment is to modify the disease, prevent complications and treat existing complications/organ damage. However, SCD control in the Nigerian state is still largely suboptimal due to her huge population, high carrier prevalence, poor public health awareness, low government/political concerns, absence of neonatal detection schemes and dedicated sickle cell centers [6][7][8]. Delayed diagnosis among affected persons, low health infrastructure, ignorance and poverty all contribute to poor outcomes in SCD care in Nigeria [5][6][7][8].
Worst still, an increasing pattern of opioid abuse, selfinflicted/treatment related complication is being observed among affected persons [9][10][11]. Opioid are mainstay in SCD pain management. However, opioids may be associated with psychologic and or physical dependence. In Nigeria, pentazocine is the most readily available opioid analgesia for moderate to severe pain.
Anecdoctal survey suggests that asides pentazocine and morphine (less available), other parenteral opioids are relatively unavailable, thus narrowing therapeutic options in the Nigerian setting. It is however undesirable that pentazocine, a synthetic opioid is associated with a new pattern of treatment related, self-inflicted medical complication [9][10][11]. As opined in a case series by Kotila et al. in Ibadan, opioid abuse is an emerging/understudied problem among SCD patients in Nigeria [9]. Similarly, Iheanacho et al. reported [11].
There is therefore a need to further characterize pentazocine abuse/misuse among affected persons living with sickle cell disease in Nigeria, in order to drive positive actions to mitigate this potential chronic menace. The objective of the study was to describe patterns of pentazocine abuse, associated medical complications as well as to identify possible clinical and socio-demographic determinants in a cohort of persons living with SCD, with a bid to proffering feasible solutions.

Methods
The study was conducted among patients receiving care at the Adult Haematology Unit of the University of Benin Teaching Hospital, a tertiary health facility in Benin City, South-South Nigeria. This study was designed as a case control study involving 50 SCD participants.
Cases included 25 known SCD patients with established history of pentazocine abuse or addiction. All cases were defined based on meeting 2 of 11 criteria (Table 1) within a year of diagnosis [12].
Control were SCD patients without documented clinical history or evidence of pentazocine addiction at the time of the study.
Participants were recruited during outpatient consultations or ward admissions, after detailed explanation of the study protocol and informed consent obtained. Relevant data including sociodemographic details, haemoglobin phenotype and details regarding pentazocine abuse (duration and frequency of use, sites of injections, needle sharing, notable physical complications of abuse) were obtained using a structured, interviewer administered questionnaire.
Questionnaire was pre-tested among 5 persons with SCD for construct and content validity, who were excluded from the main study. Data were logged and analyzed using the Statistical Package for Social Sciences (SPSS), version 16, Chicago USA. Frequencies and percentages were calculated for categorical data, with medians and interquartile range calculated for numerical data. Associations of categorical variables were tested using chi square or Fishers exact test. P values < 0.05 were considered significant.

Results
The median age of study participants was 32 years ( Table 2). Most had tertiary levels of education. About 16 (32%) studied or worked in a healthcare related field or industry. The predominant haemoglobin phenotype in the cohort was Haemoglobin SS (sickle cell anaemia).
Regarding their first knowledge of pentazocine among cases, most of them (60%) discovered the drug during acute admissions for sickle crisis, another fraction (20%) learnt about pentazocine in the course of their medical/paramedical training. On the average, 36% and 20% of the affected persons take at least 2 amp (60mg) of pentazocine on daily or at most weekly basis in the last 7 years (Table 3). Some report to take as much as 30 amps (900mg) in a single bout/binge ( Table 4).
Most of them (84%) easily secure purchase of the drug from pharmacy outlets without a need for doctor's prescription. Others when required to provide prescription forms admit raising prescriptions for themselves. Commonest sites for self-injection of pentazocine were buttocks, thigh and upper arm/deltoid area (Table 3). No report of needle sharing was observed in index study.
When asked about having to increase dose with time, 44% acknowledges some dose escalation to achieve same effect ( Table 4).
Some of the effects/complications of pentazocine misuse noted includes chronic ulcers, healed scars (not ankle ulcer or scars), abscess and deep wounds, woody legs/indurations, lymphedema, ankylosis, vascular injury and less commonly venous thrombosis (Table 4). No similar complication was observed in the control group.
Reasons given for self-indulgence in pentazocine misuse included inconvenience of regular hospital care, faster pain relief than going to hospital, suboptimal pain control in the hospital, economic reasons (less cost compared to hospital care), as well as psychologic relief (Table 5). A significant proportion, 16 (64%) affected persons had previously failed in their attempts to discontinue pentazocine abuse or even medical rehabilitations (Table 5). When tested, participants who studied or worked in a healthcare related field were found to be significantly associated with pentazocine abuse with an odd of 4.85 (Table 6). Those with frequent painful crisis also showed a significant tendency to indulge in pentazocine misuse (odds of 4.47). Pentazocine abuse was significantly associated with additional physical morbidities in sickle cell disease among index participants (Table 6).

Discussion
Pentazocine is a main-stay opioid in acute care of moderate-severe painful crisis in Nigerian SCD. Though highly desirable due to limited, locally available opioid choices, pentazocine is associated with use disorders/addictions, with myriads of physical complications, as reported in index study. Similar to other studies, most affected SCD persons were in their second to fourth decades [10,13]. This is particularly appalling as young vibrant persons embattled with a background sickle cell disease in a sub optimal care setting are further incapacitated by addictions, leading to reduced economic productivity, poor work/educational output and increased healthcare costs. This study attempted to identify key clinical and or socio-demographic determinants of pentazocine abuse. Most of these subjects had their first exposure to pentazocine while being managed at home or facility for acute pain. It is interesting to note that SCD cases with pentazocine abuse were more likely engaged in healthcare-related job consideration. This should promote good health seeking attitudes, rather than self-indulgences [9,16]. Notably, the commonest sites of self-injection were the buttocks and thigh muscles (Figure 1)  Figure 1 [17,18]. Pentazocine injected intramuscularly into all four limbs and the trunk-in one case even the back-has produced symptoms suggesting the "stiff man syndrome", with hard, tender muscles and disabling contractures.
Focal precipitation of acidic pentazocine is probably responsible.

Conclusion
Pentazocine misuse among patients with SCD in our community does occur. Hospital workers, health personnel or trainees living with SCD are more likely to abuse pentazocine indiscriminately. This trend ("pentaholism'') calls for appropriate comprehensive SCD control program to mitigate further indulgences. The management of SCD predisposes families to physical, psychosocial and financial stress, which will be invariably worsened by drug dependence. This also underscores the need for prompt triage/optimal control of acute sickle pain, institutional protocols for pain management, and strict regulations on supply of controlled drugs such as pentazocine.

What is known about this topic
• Sickle cell disease is associated with opioid abuse; • Opioid dependence and over-dosage causes physical and psychological complications.

What this study adds
• Healthcare workers or hospital personnel living with SCD are at a greater tendency to abuse Pentazocine.

Competing interests
The authors declare no competing interests.

Authors' contributions
AA conceived and designed the study, analyzed the data and partook in manuscript development. OA engaged in data collection and manuscript development. ND took part in manuscript development and critical appraisal. MO was part of data collection, manuscript writing. All authors read and approved the final draft for submission.

Acknowledgments
Authors would like to thank all persons living with sickle cell disease who participated in this study. Table 1: substance abuse disorder, international statistical classification of disease and related health problems, ICD -10 Table 2: bio-data of the study participants Table 3: details of pentazocine abuse among cases Table 4: practices regarding pentazocine self-use Table 5: reasons for pentazocine abuse    Tolerance and use of progressively la rger amounts to obtain the same desired effect Withdrawal symptoms when not taking the substance NB: tolerance and withdrawal are not needed to make diagnosis