Tissue Necrosis: A Burden of Pentazocine Abuse in South East Nigeria

Abstract

Background:

Tissue necrosis from pentazocine abuse is becoming a burden in our environment. Pentazocine is an opioid of the benzomorphan class. It is commonly used for post-traumatic and postoperative pain and vaso-occlusive pain of sickle cell disease (SCD). Its prolonged use can lead to addiction and may result in severe injection site necrosis, often worsened by infection due to a lack of aseptic principles during administration. Although pentazocine is a controlled drug in our environment, it is readily available.

Objectives:

To review patients with tissue necrosis from pentazocine injection, share the challenges in their management, and proffer solutions.

Materials and Methods:

Clinical summaries of patients with tissue necrosis and ulcers due to pentazocine addiction were reviewed.

Results:

Twenty-five patients, comprising nine females and 16 males aged 22–61 years, were recorded. Twenty had SCD, while five had other underlying conditions. The duration of abuse was 1–16 years, while the average maximum daily dose was 348.75 ± 346.04 mg. Most patients used multiple sites for injection. Lesions included abscesses, tissue necrosis with ulcers, lymphoedema, exposed necrotic bones, and osteomyelitis. Most had multidisciplinary care. The outcome of wound care was good in two. Three had major limb amputations, four died, three signed against medical advice, six were still receiving care while seven were lost to follow-up. None was completely weaned from the drug at the time of this report.

Conclusion:

Rising cases of tissue necrosis from pentazocine abuse are disturbing. Treatment is frustrating. Concerted efforts at prevention should be made to stem the tide.

Introduction

Pentazocine is an opioid of the benzomorphan class.[1,2] It is commonly used for the relief of moderate to severe pain arising from various clinical conditions such as trauma, early postoperative period, and pain of vaso-occlusive crisis of sickle cell disease (SCD).[1,2] In most cases, it is used for a short duration, but in some cases, the course may be repeated or prolonged.[1,2] Prolonged use often results in dependence and addiction.[1,2] It was initially thought to be nonaddictive, and the World Health Organization (WHO), through its expert committee on drug dependence, had recommended that it should not be subjected to narcotic control.[1,2] As a result, the drug was made readily available to the public.[1,2] Its abuse and dependence potential have remained controversial. However, there have been several reports of pentazocine abuse, dependence, and addiction.[2,3,4] Internationally, pentazocine is currently classified as a schedule III drug, which shows greater potential for abuse and dependence.[5] Similarly, in Nigeria, it is contained in schedule III of the list of psychotropic substances in the national policy document for controlled medicines and its implementation strategies.[6] However, the control of the drug in Nigeria is seriously in doubt, as it is still readily available over the counter.[7]

With dependence and addiction, victims who obtained the drug based on medical indications resort to self-injection without the knowledge of safety measures required for such procedures.[7,8,9,10] The results are tissue infection and necrosis.[7,8,9,10] This is becoming a burden in our environment as reports show that treatment of the addiction is often unrewarding, making tissue infection and necrosis unrelenting and recurrent.[7,10] This results in significant disability, morbidity and mortality.[7,10]

The aim of this study was to review patients who presented with tissue necrosis and ulcers as a result of pentazocine abuse, share the challenges in their management, and proffer possible solutions.

Patients Methods

This study was a mixed retrospective and prospective observational study. Clinical summaries of patients with tissue necrosis and ulcers due to pentazocine addiction who presented to any of four tertiary health institutions in the southeast region of Nigeria were obtained within a 5-year period (retrospective; 2017–2020 and prospective; 2021–2022). Information obtained included the biographic data, disease condition that necessitated the use of pentazocine, daily dose and duration of use, the site of the injection and the lesions, and treatment outcome, as well as clinical photographs. Ethical approval was obtained from research ethics review committees of the institutions: ESUT Teaching Hospital, Enugu, National Orthopedic Hospital, Enugu, University of Nigeria Teaching Hospital, Enugu, Enugu state and Alex Ekwueme Federal University Teaching Hospital, Abakaliki, Ebonyi State Informed consent to use images was obtained from the patients while consent to reproduce published images was obtained from the copyright owners. Data were subjected to statistical analysis using PSPP4Windows® computer software version 1.4.1, 2019.[11] The results were presented in prose, charts, and tables.

Results

A total of 25 patients presented with tissue necrosis and ulcers due to self-injection of pentazocine within the period under review. About 80% (20) of these were presented in the past 2 years. They were made up of 16 males and nine females aged between 22 years and 61 years [Table 1], with a mean of 35.5 ± 11.64 years.

Table 1.

Age distribution of patients abusing pentazocine

Age groups in years	Frequency	Percentage
0–9	0	0
10–19	1	04.00
20–29	10	40.00
30–39	10	40.00
40–49	1	04.00
50–59	2	08.00
60–69	1	04.00
Total	25	100

Nine patients representing (36%) were students, five (20%) were school dropouts from the effects of the drugs, three (12%) were artisans, three (12%) health professionals, two (8%) civil servants, one (4%) a legal practitioner, one (4%) a policeman, and one (4%) a trader.

Twenty patients (80%) had SCD, while others had various clinical conditions [Figure 1].

Figure 1.

Distribution of underlying disease in symptomatic patients abusing pentazocine. (SCD, sickle cell disease; PUD, peptic ulcer disease)

Patients abused the drug for 1–16 years with a mean of 7.60 ± 6.10 years. The duration of abuse had some effects on tissue damage and outcome. The patients that had good wound healing outcomes abused the drug for less than 5 years, while two out of the three patients that had major limb amputations abused the drug for 10 and 15 years, respectively. Similarly, half of the patients who died abused the drug for 16 years. However, the effect of duration of abuse on overall outcome was not statistically significant (P = 0.51).

The average maximum daily dose used by the patients was 348.75 ± 346.04 mg and a range of 120 to 1,500 mg. Administration was self-injection by intramuscular, subcutaneous, and often incorrect intravenous routes. Site of injection were mostly the forearms, thighs, legs, buttocks, and arms in order of frequency [Table 2]. Most of the patients used multiple sites for injections [Figure 2], and the lesions were located at these sites, which are often bilateral [Figures 3,4,5,6].

Table 2.

Distribution of lesions in symptomatic patients abusing pentazocine according to anatomic site

Site of lesions	Frequency	Percentage
Thighs	10	26.32
Forearms	15	39.47
Legs	7	18.42
Buttocks	4	10.53
Arms	2	05.26
Total	38	100

Figure 2.

Picture showing multiple sites of injection and lesions involving all four limbs

Figure 3.

(A) Picture showing ulcer on oedematous left leg with raised edges, nodular floor, and areas of necrosis (reproduced with permission).[7] (B) Picture showing ulcer on oedematous right leg with areas of necrosis (reproduced with permission).[7] (C) Picture showing ulcer left leg after wound bed preparation (reproduced with permission).[7] (D) Picture showing ulcer on the right leg after wound bed preparation (reproduced with permission).[7] (E) Picture showing both legs after split-thickness skin grafting (reproduced with permission).[7] (F) Picture showing lesions on the left upper and lower limbs on resumption of injection 2 years after initial treatment

Figure 4.

(A) Picture showing lesions on the right thigh with full-thickness skin necrosis. (B) Picture showing lesions on the left thigh with full-thickness skin necrosis

Figure 5.

(A) Picture showing right thigh lesion with exposed necrotic femur and scars on the left thigh. (B) Picture showing above-knee amputation stump following the pathological right femoral fracture

Figure 6.

Picture showing bilateral forearm lesions with lymphoedema

The lesions recorded included multiple ulcers in all patients, associated lymphedema in four patients, osteomyelitis in five patients with exposed bones in three, and discharging sinuses in two. One of the patients had a pathological fracture of the femur. Multiple abscesses and necrotizing fasciitis with soft tissue necrosis, including tendons, were also recorded and were diagnosed clinically. Wedge biopsy was done in a case [Figures 3A and B] where there was a clinical suspicion of malignancy, but histology revealed chronic inflammatory features. Most of the patients had initial in-patient treatment, though there was marked reluctance to accept admission for fear of stopping the drug.

Treatment

Care was by a multidisciplinary approach, with plastic surgeons, psychiatrists, clinical psychologists, nurses, orthopedic surgeons, pathologists, and hematologists making up the team depending on the needs of the patients. Soft tissue/wound care involved debridement where indicated, appropriate use of various dressing agents, including negative pressure wound therapy, and provision of cover using split-thickness skin graft in most cases. Sinusectomy and curettage were done in the presence of osteomyelitis, while amputation was offered where limb salvage could not be achieved, as in patients with exposed necrotic femur [Figure 5A] and pathological fracture, gangrene of the upper limb and extensive necrosis of soft tissues of the dorsum of hand and wrist including tendons, ligaments, joint capsule as well as some carpal bones.

Dependence was treated in two phases: detoxification/stabilization and rehabilitation/relapse prevention phase. In the detoxification phase, we could not use an opioid agonist (methadone) or partial antagonist (buprenorphine); instead, we used the calming effect of antidopaminergic, antipsychotic agents: chlorpromazine, in addition to the effect of tricyclic antidepressant (amitriptyline). For rehabilitation/relapse prevention, patients were engaged with insight-oriented psychotherapy, cognitive behavioral therapy, social skill training, and group drug therapy. However, all the health institutions where they were managed lacked a conducive environment for the treatment of dependence as patients still had contacts that could supply them with the drugs, while designated rehabilitation centers lacked the required multidisciplinary team.

Outcome

The outcome of wound care was good in two patients. Three had major limb amputation (one above knee; [Figure 5B], one above elbow and one below elbow), four died from the complications (hemorrhage and sepsis), three were discharged against medical advice, six were still receiving care mostly on out-patient basis while seven were lost to follow-up. None was completely weaned from the drug at the time of this report. One who was previously reported to have been weaned[7] relapsed with fresh lesions after 2 years, presenting twice to the hospital [Figure 3F].

Discussion

Tissue necrosis following pentazocine abuse, which was previously sparse in our subregion, appears to be on the increase.[7] In our study, over the past 5 years, 25 cases were recorded in four tertiary hospitals in the southeast region of Nigeria. They were made of 16 males and nine females with a male-to-female ratio of 1.8:1, which is similar to reports by Iheanacho et al.[12] in Benin City with a male-to-female ratio of 2:1 but a contrasting 1:4 male-to-female ratio reported by Otene et al.[10] in Asaba, all in south-south Nigeria. The most affected age group in this study was the mid-thirties, which is similar to the findings in both studies.[10,12] The socioeconomic effects of addiction go beyond the victims of the addiction as the actively productive age groups are affected and indirectly their dependents.[13,14] This is even more worrisome as a good percentage of the victims are professionals, including health professionals. Some of the victims dropped out of school because of the addiction.

The majority of our patients were living with SCD, which is consistent with findings in other similar studies and reports.[7,10,12] This is understandable as pentazocine ranked second after NSAIDs grouped together as a drug of choice in the management of pains in sickle cell patients, as reported by Madu et al.[13] Pentazocine was also the second post-operative analgesic after pethidine in a study of postoperative pain management by Ogboli-Nwasor.[15] This is evidence of the rampant use of the drug in Nigeria. Although there is a wide disparity in general opioid consumption in different geographic regions of the world, with advanced countries like Canada consuming much more than low-income countries like Nigeria,[16] pentazocine is no longer in frequent use in most developed countries and in some countries only available in oral formulations combined with other drugs.[17]

Although SCD is the most common clinical condition necessitating initial use of the drug, any condition associated with moderate to severe pain can be a culprit.[10,12,18] We noted other conditions such as postcholecystectomy, gunshot injuries, PUD, and lumbar spondylosis. Similarly, Mudrick et al.[12] reported necrotizing soft tissue infection and florid osteomyelitis following the use of the drug for migraine headaches in a patient who incidentally was from Nigeria. Kumar et al.[18] reported pentazocine-induced contractures following its use for abdominal pain. Otene et al.[10] also recorded other clinical conditions besides SCD. This is another evidence of the rampant use of the drug in our environment. Most patients in our series started the use of the drug from an initial legitimate prescription in health facilities. The situation is similar to several previous reports.[7,10,12,17] The implication is that if the drug is prescribed less often, the number of persons with the chance to abuse the drug will be reduced.

After the initial use of the drug based on medical indications, patients subsequently procure it on their own. It is appalling that although pentazocine is a controlled drug,[6] it is readily available over the counter, thereby creating a pathway for abuse.

The recommended maximum daily parenteral dose of pentazocine is 360 mg.[1] The maximum daily dose used by our patients ranged from 120 to 1,500 mg. This dose range is much higher than doses reported to have caused local complications in literature[15] and will require repeated injections to administer.

Such repeated and prolonged high doses of the drug result in local tissue changes that range from induration, necrotizing tissue infections, ulceration, and myofibrosis to florid osteomyelitis.[1,8,16,17,18] Almost all these reported local tissue complications were observed in our study. Various mechanisms have been adduced for this phenomenon. Pentazocine is an acidic drug that is more soluble in an acidic medium and precipitates in a neutral or alkaline medium such as the interstitial fluid.[17,19] The precipitates induce chronic inflammatory processes that result in vascular thrombosis, necrosis, and fibrosis. This is worsened by contamination by microorganisms, leading to infection as injections are given without knowledge of or recourse to proper technique and asepsis.

Most of our patients receive care in centers that have the expertise for appropriate multidisciplinary care but lack a conducive environment for rehabilitation, while facilities that are designated for rehabilitation lack the requisite expertise for the management of tissue complications. This may have contributed to the failure in weaning most of the patients from the drug. In patients who are unlikely to withdraw from the drug successfully in the community, it is recommended that they undergo short-term in-patient or residential treatment in a controlled and medically supervised environment.[20] This involves a detoxification phase using opioid analogs/agonists such as methadone or partial agonists such as buperophenone and rehabilitation.[21] This poses a major challenge in our environment, as these drugs are not readily available in our centers, and we have to use substitutes. However, the drug may be available in dedicated rehabilitation centers, which are scarce, poorly funded, and often expensive.[22] Besides, soft tissue complications are often life-threatening, and our patients were managed in facilities where medical supervision was possible, but control was very difficult. Most of the patients still had contacts that secretly supplied them with the drug.

The overall outcome of the treatment of our patients is at best disappointing. Those who survive the acute episode of tissue complications continue to inject the drug at the least opportunity they get, thereby repeating the cycle. It is thus becoming a burden as new cases present while old ones show no likelihood of getting a permanent cure.

We recommend that practitioners should adopt alternative nonaddictive analgesics such as NSAIDs in place of pentazocine. Where it must be used, oral formulations may reduce the need for injections and, hence, tissue necrosis.

Regulatory or enforcement authorities can do a lot more to enforce already existing guidelines on the prescription, availability, and use of controlled drugs, particularly pentazocine. Pentazocine should be categorized as a schedule II controlled drug and treated as a dangerous drug of addiction (DDA), such as pethidine and morphine. If it is stored, distributed, and used as other DDAs, its use will be restricted and administration will be done by professionals under aseptic conditions, reducing both dependence and local tissue complications. There is an increasing need for concerted efforts by all stakeholders to stem the tide.

Given the burden of SCD in our country, a nationwide study or review is recommended to determine the actual burden of pentazocine-induced tissue injuries.

Limitation

The sample is small. However, the physical, economic, and psycho-social burden of the condition on the victims and their families, as well as the demand on the practitioners, are so enormous that it merits discussion.

Contribution details

UCM: concept, design, data collection, literature search, manuscript preparation, and critical review, approved final version, responsible for the integrity of the work and guarantor. GO: data collection, literature search, critical manuscript review, approved and agreed to be accountable for the final version. ORO: provision of data, critical review of the manuscript, approved and agreed to be accountable for the final version. IEE: provision of data, critical review of the manuscript, approved and agreed to be accountable for the final version. GMO: provision of data, critical review of the manuscript, approved and agreed to be accountable for the final version. SRO: data analysis, critical review of the manuscript, approved and agreed to be accountable for the final version. ICU: study design, draft of manuscript, approved and agreed to be accountable for the final version. MSE: provision of data, critical review of manuscript, approved and agreed to be accountable for the final version. WOO: provision of data, critical review of manuscript, approved and agreed to be accountable for the final version.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.