Nalbuphine: an underrecognized battlefield analgesic and its utilization in combat care and peripheral areas

Abstract

Battlefield injuries result in acute and severe uncontrolled pain, which can be reduced with the early use of analgesia. Apart from pain, battlefield injuries may also cause significant morbidity and a prolonged period of absence from active duty. Traditionally available opioids are known to cause various undesirable side effects such as respiratory depression that may worsen the condition of an already injured combatant. Nalbuphine is an opioid agonist-antagonist and has been increasingly used for postoperative analgesia over the last decade. In India, it is the only opioid analgesic that does not come under the Controlled Substances Act at the time of this publication. In today's world, where nalbuphine is being recommended for acute pain worldwide, its use in the Indian combat scenario needs to be conceptualized at the medical officer level (primary caregiver). This conceptualization will be discussed in detail in this review article.

Introduction

Pain resulting from battlefield injuries (BFIs) can be severe and unbearable.¹ Bullets, shrapnel, and blasts may cause various disabling injuries to combatants, which in turn may lead to chronic pain syndromes, such as neuropathic pain, degenerative arthritis, and lumbago.² Hemorrhage and neurogenic shock are common in combat zones and are probably the most common causes of mortality in a war scenario.^3,4 Literature reveals that almost 80% of American combat soldier casualties transported from the Iraq war suffered from severe pain.⁵ Pain can potentially aggravate morbidity, leading to further deterioration of the patient. Early use of analgesia apart from being the standard protocol for the management of neurogenic shock after BFI, has also been shown to improve outcomes.^6,7

Realizing the importance of early and adequate analgesia, a myriad of options have been used in the combat setting. Battle Field Nursing Assistants generally have access to both opioid and non-opioid analgesics. However, non-opioid analgesics often do not suffice for adequate analgesia following BFIs. Morphine and fentanyl are effective opioid analgesics and are commonly used in prehospital settings, for both combat and civilian casualties.⁸ However, conventional opioids come with various side effects, including nausea, vomiting, itching, and respiratory depression, that may worsen the effects of hypovolemic shock due to ongoing bleeding.⁹ On the flip side, early effective pain control for BFI is important for a successful recovery. A further point of concern about the use of conventional opioids is the present opioid epidemic in the United States, which is also quite prevalent among military veterans. Most veterans with BFIs are on prescription opioids for chronic pain, usually described as pain lasting more than 3 months. Toblin et al, in their study, have demonstrated that chronic pain and opioid use have been found to be higher in veterans compared with general population.¹⁰ Data reveal that almost 70,000 US military veterans were treated for opioid use disorders in 2016.¹¹ Opioid-related mortality, abuse, and overdose rates are all significantly higher among veterans.¹² In India as well, 2.1% of the country's population uses opioids, of which 0.9% are on pharmaceutical opioids. Its usage constitutes three times the global average.¹³ These concerns have generated an increased interest in newer opioid derivatives, which may offset some of the deleterious effects of conventional opioids. A literature search was therefore carried out to examine the potential for the use of newer opioid derivatives in the battlefield. To detect all available studies on words “battlefield analgesia,” “analgesia in trauma,” and “war analgesia,” we conducted a systematic literature search in PubMed, Google, Scopus, and Google scholar to write this narrative review.

Nalbuphine—the drug

Nalbuphine is a semi-synthetic opioid analgesic of the phenanthrene series. It was synthesized in 1965 and marketed by Du Pont Pharmaceuticals in 1979 under the brand name NUBAIN. It was created to provide analgesia without the adverse effects of pure opioid agonists. It is the only opioid analgesic that does not come under the Controlled Substances Act.

Nalbuphine hydrochloride's International Union of Pure and Applied Chemistry name is [(−)-17(cyclobutylmethyl)-4, 5α-epoxymorphinan-3, 6α, 14-triol hydrochloride]. It is an antagonist at mu-opioid receptors and an agonist at kappa-opioid receptors. Its analgesic potency is essentially equal to morphine when administered via intramuscular (IM) or subcutaneous (SC) routes up to a limit of 30 mg. Because of its high first-pass metabolism, an oral dose is only one-fourth as potent as an intramuscular dose. The onset of action is within 2–3 min after intravenous (IV) administration and less than 15 min following SC or IM injection. The duration of analgesia ranges from 3 to 6 h. It is lipophilic and has a large volume of distribution. It is metabolized in the liver to N-hydroxycetocyclo butyl methyl nornalbuphine (major metabolite) with a plasma half-life of 2–3 h. Its clearance mainly depends on hepatic blood flow, with the elimination half-life being 3–6 h, as it has a high hepatic extraction ratio of 0.5–0.7.¹⁴

It is indicated for the management of pain severe enough to require an opioid agent and has also been used for preoperative and postoperative analgesia, obstetrical analgesia, or as a supplement for anesthesia (this requires higher doses and anesthesia expertise).^14,15 Apart from these approved indications, nalbuphine also has many off label indications, including the treatment of opioid-induced respiratory depression and urinary retention and pruritus secondary to neuraxial opioids.

The usual suggested dose is 10 mg for a 70 kg adult when administered SC, IM, or IV, which may be repeated every 3–6 h. In opioid-naive individuals, the recommended single maximum dose is 20 mg, with a maximum total daily dose of 160 mg. If used as an anesthesia supplement, the doses are 0.3 mg/kg to 3 mg/kg IV to be administered over a 10- to 15-minute period with maintenance doses of 0.25–0.5 mg/kg as a bolus when needed.^14,15

At commonly used doses (≤10 mg), side effects are uncommon and/or mild and are mostly limited to non-specific features, such as sedation, sweating, and headache. At much higher doses (≥70 mg), psychotomimetic side effects (e.g. dysphoria, racing thoughts) can occur. Anaphylactic reactions have also been described and may require urgent, supportive medical management.

Although it was initially designed to countermand the undesirable effects of conventional opioids, it causes comparable respiratory depression to equianalgesic doses of morphine because of a reduction in the responsiveness of the brainstem respiratory centers to increase in P_aCO₂ levels.¹⁴ However, a vital point in its favor is that the respiratory depression due to nalbuphine exhibits a ceiling effect with doses beyond 30 mg causing no further analgesia or respiratory depression. It is also important to note that the respiratory depressant effects can be reversed with naloxone if needed. In addition, studies have also demonstrated that IV nalbuphine helped reduce the respiratory depression caused by the administration of intrathecal morphine in postthoracotomy patients (Baxter). However, alternative agents should be used in patients with significant respiratory depression or patients with diminished respiratory reserve, severe bronchial asthma (especially when resuscitative equipment is not available), patients with features suggestive of intestinal obstruction, and patients with a known hypersensitivity to the drug. When administered concurrently with other drugs with the potential for central nervous system depression, nalbuphine can cause profound sedation, respiratory depression, coma, and even death. Patients will require monitoring for respiratory depression at the initiation of therapy or after an increment for the first 1–3 days. Caution is also to be taken in adjusting the dose in hepatic impairment, as the drug is primarily metabolized in the liver.

Unlike other mixed agonist-antagonists, 10 mg nalbuphine when administered to patients with acute myocardial infarction/stable coronary artery disease does not produce an increase in cardiac workload, pulmonary arterial pressure, or systemic blood pressure. However, there is some amount of peripheral vasodilatation and histamine release associated with its use. The histamine release may cause pruritus, flushing, red eyes, and sweating. The peripheral vasodilatation may, on occasion, be severe enough to cause hypotension. In addition, nalbuphine use will cause miosis, irrespective of the presence of external light. Extreme miosis also known as ‘pinpoint’ pupils is suggestive of opioid overdose but is not diagnostic for the same (it may occur with pontine lesions also). Also, if the overdose has led to hypoxia, the mydriatic effect will overcome the miosis.¹⁶

Another pertinent point to be noted is that concurrent use of agonist/antagonist analgesics with mu-opioid agonists may precipitate withdrawal symptoms and/or reduce analgesic efficacy. Abrupt discontinuation after prolonged use may also lead to withdrawal symptoms. Also, it may precipitate withdrawal if the patient is a chronic opioid user.

Legal status of nalbuphine (abroad and in India)

Nalbuphine was initially under Schedule II of the USA's Controlled Substances Act, which included drugs medically used but with high potential for abuse.¹⁷ Later, it was removed entirely from the Controlled Substances Act in 1973 and is no longer regulated. This was in light of its extremely limited potential to generate euphoria, unlike the pure opioid agonists.

In India, it is available over the counter, as it does not come under Schedule X of the Drugs and Cosmetics Rule or the Essential Narcotic Drugs listed by the Central Drug Standards and Control Organisation.

Potential for abuse

There are very few reports suggestive of nalbuphine addiction.¹⁸ However, despite the lower likelihood of causing euphoria, nalbuphine addiction/dependence is possible even at recommended dosages, such as when patients are placed on long-term nalbuphine therapy for chronic pain.¹⁹ The risk is higher in patients with a history of substance abuse (either personal or family history of abuse) or mental illness. It is important to note that addiction, dependence, and tolerance to nalbuphine are generally seen only with chronic opioid therapy and have not yet been defined in the setting of acute care.

The military use of analgesics—present scenario

The global literature on the military use of analgesics is skewed toward the United States of America and North Atlantic Treaty Organization countries. In addition, their doctrine of battlefield analgesia is in the public domain.²⁰ The data from Afghanistan in 2012–2013 have revealed a predominance of ketamine use closely followed by morphine and fentanyl.²¹ Ketamine was occasionally combined with morphine. The high prevalence of morphine use was more because of its availability and familiarity rather than a judicious assessment of the circumstances. In addition, the use of transmucosal fentanyl with a median dose of 800 mcg was also noted. Noting the high use of IM morphine and its imprecise analgesic effects and the generally imperfect science being followed with regard to battlefield analgesia, the US Army refined its practices and evolved its Tactical Combat Casualty Care System (TCCCS) into its present state.²²

In brief, their present system closely mimics the World Health Organization stepladder approach to pain management,²³ wherein the analgesic regimens are personalized to the requirements of the patients. The salient points of the same are elucidated below.

• •For mild to moderate pain—paracetamol (Tylenol) in higher doses of 1300 mg 8 hourly and meloxicam in a single dose of 15 mg once daily.
• •For moderate to severe pain—oral transmucosal fentanyl citrate 800 μg lozenges were used when the patient is devoid of shock or distress and devoid of risks for the same or doses of morphine 5 mg IV dose repeated every 10 min if needed. However, if the patient had signs of shock or distress, ketamine 50 mg IM or 20 mg slow IV/IO was used and repeated as desired until analgesia was achieved, or nystagmus was noted.

Two things of note are that the TCCCS recommends naloxone be made available if opioids were being used and to not preclude the use of ketamine in ocular trauma. In addition, they justify the use of ketamine in severe traumatic brain injury (a traditional contraindication) using the justification that if the patient can complain of pain, the brain injury may not be severe enough to preclude its use.

Nalbuphine in the Indian military scenario

Consequent to the Indian military not having fought a conventional war in over two decades and mostly being engaged in low-intensity combat operations, this kind of large-scale data is lacking. The authors have noted the use of morphine, pethidine, and tramadol in cases of trauma with moderate to severe pain in battlefield casualties. In addition, it was noticed that there was a severe lack of experience among the front-line medical teams with drugs such as ketamine and fentanyl.

It is important to note that the production and distribution of morphine and other opioids in India are strictly regulated under the Narcotic Drugs and Psychotropic Substances act and emergent purchases are usually not possible. In addition, tramadol and ketamine are also regulated under Schedule X of the Drugs and Cosmetics Act. Notably, nalbuphine as an agent is free from these limitations.

The added advantage is that when compared with morphine, which requires careful dilution from its 15 mg/mL ampoule to a 1.5 mg/mL solution before use, a 10 mg/mL vial of nalbuphine requires no dilution, as it is the dose that is required to be given initially. Undiluted morphine when administered in haste, which can happen on the battlefield, can lead to disastrous consequences.

Nalbuphine in the battlefield

Although the properties of nalbuphine encouraged its use in trauma and postoperative patients, its use in the military setting was limited by the fact that military trauma varied significantly from civilian trauma, not least in the fact that military trauma occurs in a resource-strapped setting. With data for its use being initially limited to well-equipped hospitals, it could not be extrapolated to assess the risk/benefit in exsanguinating patients on the battlefield. This prompted a randomized controlled study, which showed promising results for the use of nalbuphine in combat trauma as well.¹⁵

In a study of 46 patients in one Maryland county (Anne Arundel) to ascertain if nalbuphine could be safely administered to patients suffering moderate to severe pain in the prehospital setting, it was reported to be safe for IV use by paramedical staff in the prehospital scenario.²⁴ In a metanalysis, the analgesic efficacy of nalbuphine was found to be comparable to morphine, but nalbuphine provides a better safety profile than morphine in the aspect of certain side effects, especially related to pruritus and respiratory depression. The reported incidences of pruritus, nausea, vomiting, and respiratory depression were significantly lower in the nalbuphine group compared with the morphine group, and the pooled risk ratios (RRs) were 0.78 (95% confidence interval [CI], 0.602–0.997; P = 0.048) for nausea, 0.65 (95% CI, 0.50–0.85; P = 0.001) for vomiting, 0.17 (95% CI, 0.09–0.34; P < 0.0001) for pruritus, and 0.27 (95% CI, 0.12–0.57; P = 0.0007) for respiratory depression.²⁵ It was also found to be safe in the pediatric population, with a larger margin of safety and less frequent nausea and vomiting compared with other opioids.²⁶ It produces adequate analgesic and sedative effects, and because of the ceiling effect, it is devoid of severe respiratory depression at effective analgesic doses.

Concept of carrying nalbuphine vial in forward areas

Administration of nalbuphine within minutes of trauma can help attain the best possible pain relief for the patient. Various studies in postoperative patients and trauma victims reveal that nalbuphine should be given as soon as possible.27, 28, 29 Extrapolation of this concept to combatants would mean that nalbuphine should be administered on the battlefield before evacuation to forward surgical centers. Every medical officer/nursing assistant should initiate treatment with nalbuphine, along with the first IV crystalloid. This will also help reduce the aggravation of pain while the patients are being shifted to the forward echelon and can help achieve a pain-free postinjury period.

Recommendation

Nalbuphine is an United Stated Food and Drug Administration (FDA)-approved agent indicated in patients with moderate to severe pain. Its use has also been extended to the treatment of labor pain, neuraxial opioid-induced pruritus, and opioid-induced urinary retention and respiratory depression. Its use in trauma victims can help attain better pain-free periods with minimal adverse effects. Care should be taken in patients with concomitant respiratory depression, as it may cause respiratory arrest. However, this possible increase in the incidence of respiratory depression could be offset by the mortality benefit by the administration of nalbuphine in combat trauma patients. However, larger studies are required, especially in victims of battlefield injuries, to prove its effectiveness in the modern-day war scenario. With regard to Indian military scenario, we suggest that nalbuphine be incorporated into the Priced Vocabulary Medical Stores list and gradual training be provided to front-line medical personnel in its use. It may also be used in peacetime as a morphine substitute, saving the hospital's valuable time and money in complying with the regulations on opioid use. There is also a need for a standardized analgesic policy for battlefield analgesia tailored to our circumstances and the availability of medication.

Disclosure of competing interest

All authors have none to declare.