|Year : 2015 | Volume
| Issue : 3 | Page : 89-95
Safety of nalbuphine on neural tissues of rats and its efficacy in the treatment of acute herpetic pain in children with acute lymphoblastic leukemia
Josef Z Attia1, Maha Y Kamel2, Rehab K Yousef3
1 Department of Anesthesiology; Intensive Care Unit, Faculty of Medicine, Minia University, Minia, Egypt
2 Department of Pharmacology, Faculty of Medicine, Minia University, Minia, Egypt
3 Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt
|Date of Submission||27-Jul-2015|
|Date of Acceptance||19-Aug-2015|
|Date of Web Publication||30-Dec-2015|
Josef Z Attia
PhD, Department of Anesthesiology, Faculty of Medicine, Minia University, 61111 Minia
Source of Support: None, Conflict of Interest: None
Acute lymphoblastic leukemia (ALL) has been previously shown to cause severe impairment in immunity, in turn making children more susceptible to viral infections, especially herpes zoster, which manifests with severe pain.
Materials and methods
The main purpose of this study was to experimentally evaluate the safety of nalbuphine on the neural tissues of rats treated with nalbuphine at doses of 0.5, 1, 2, 4, and 5 mg/kg injected intrathecally every alternate day for 14 days, and to determine the efficacy of caudal injection of nalbuphine with a minimal dose of oral paracetamol as an analgesic in pediatric patients with ALL suffering from acute herpetic pain.
The results revealed that nalbuphine exerted no pathological changes in either the cerebellum or the spinal cord. However, the protective effect of nalbuphine with the minimal dose of paracetamol was associated with a significant analgesic effect in ALL children. Its analgesic effect was assessed by means of the Facial Pain Scale and the behavioral pain assessment scale, and motor block assessment was made on the basis of the Bromage score.
Caudal nalbuphine with a minimal dose of paracetamol has adequate analgesic effect on acute herpetic pain in pediatric patients with ALL, without any pathological changes in the cerebellum and spinal cord.
Keywords: Herpes zoster, motor block, nalbuphine, pain assessment
|How to cite this article:|
Attia JZ, Kamel MY, Yousef RK. Safety of nalbuphine on neural tissues of rats and its efficacy in the treatment of acute herpetic pain in children with acute lymphoblastic leukemia. Res Opin Anesth Intensive Care 2015;2:89-95
|How to cite this URL:|
Attia JZ, Kamel MY, Yousef RK. Safety of nalbuphine on neural tissues of rats and its efficacy in the treatment of acute herpetic pain in children with acute lymphoblastic leukemia. Res Opin Anesth Intensive Care [serial online] 2015 [cited 2018 May 20];2:89-95. Available from: http://www.roaic.eg.net/text.asp?2015/2/3/89/172801
| Introduction|| |
Acute lymphoblastic leukemia (ALL) is a malignant disorder of lymphoid progenitor cells, representing one-third of all malignant tumors that affect children, with its peak prevalence between the ages of 2 and 5 years .
There is a close link between ALL and immunodeficiency. Despite the presence of a high count of white blood cells, ALL patients are immunosuppressed because of dysfunction of white blood cells due to interaction with leukemic cells, hypo-γ-globulinemia resulting from the suppression of Ig secretion, bone marrow infiltration resulting in bone marrow failure (pancytopenia), or because of a large dose of multiple chemotherapies used to treat these types of tumors . Further, these patients are more susceptible to viral infections, especially herpes zoster (HZ) . The incidence of HZ among lymphatic leukemia patients is about 4.9-0.9% . Almost one-third of seropositive children have been seen to have HZ during primary chemotherapy. Of those treated on high-risk protocols, more than half have one or more eruptions during the course of treatment. The risk for complicated HZ is low, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions .
The varicella zoster virus remains latent because of varicella zoster virus-specific cell-mediated immunity. Reactivation of the virus occurs following a decrease in virus-specific cell-mediated immunity. The virus travels down the dorsal root resulting in characteristic pain and skin lesions along the affected root. Acute herpetic pain is severe, resulting in further agony in already exhausted children .
Acute herpetic pain treatment includes a mixture of acyclovir, an antivirus that can be applied intravenously or orally, and analgesics. The most commonly used are NSAIDs, which carry the risk for bleeding due to thromboasthenia, and renal impairment due to infiltration of kidneys with leukemic cells as a result of chemotherapy, especially in high-risk ALL patients . Opiate analgesics provide effective pain relief and are a standard of care for control of mild to severe pain in both adult and pediatric populations .
Most clinically useful opioids achieve their analgesic effect through the binding and activation of μ-opioid or k-opioid receptors, whereas other opioid agents, such as nalbuphine (mixed opioid agonist-antagonist), achieve significant analgesia through the activation of the k-opioid receptor alone, with no effects of μ-receptors .
When nalbuphine binds to μ-receptors, it serves only to competitively displace other μ-agonists from the receptor, without displaying any agonist activity itself. At μ-receptors, nalbuphine has only antagonist effects, similar to those of naloxone. When nalbuphine binds to k-receptors, however, it has an agonist, activating effect. This pattern of binding and effects defines nalbuphine as a mixed agonist-antagonist .
The use of nalbuphine as an analgesic agent yields satisfactory analgesia that covers mild to moderate pain, with a low incidence of side effects of a μ-opioid receptor agonist, such as respiratory failure .
Pediatric regional anesthesia has gone through significant development in recent years, with advancements in safety, pharmacology, and block techniques. There is increasing interest in regional anesthesia in pediatrics beyond the common caudal, epidural, or spinal type . Caudal anesthesia is one of the most popularly used regional blocks in children. This technique is useful as an adjunct during general anesthesia and for providing postoperative analgesia after infraumbilical operations .
In view of the aforementioned information, the present study was planned to assess the safety of the mixed agonist μ-k nalbuphine on neural tissues of experimental rats, excluding any pathological change, and to determine the efficacy of nalbuphine as an analgesic administered through caudal injections in pediatric ALL patients with renal impairment who are suffering from acute herpetic pain, instead of a high dose of NSAIDs or opioids.
| Materials and methods|| |
Two studies were performed.
In Study 1, the safety of nalbuphine HCl on neural tissues in experimental rats was evaluated.
In Study 2, we planned to assess the efficacy of caudally administered nalbuphine HCl in children who had received chemotherapy for treatment of ALL with mild renal impairment complicated by HZ.
Animals and experimental design
Adult albino male rats (Sprague-Dawley strain; 250-280 g) obtained from the animal house of the National Center of Research, El-Giza, Egypt, were used in the experiments. The rats were allowed to acclimatize to the animal house conditions (12 h lighting cycle and a temperature of 25 ± 2°C) for 1 week and were given free access to a standard pellet diet and water ad libitum. All experimental procedures were conducted according to the ethical standards approved by the Institutional Animal Ethics Committee guidelines for animal care and use, Minia University, Egypt. The animals were randomly divided into 10 groups of eight animals each. Five control groups of rats received saline injections in identical regimens to the analgesic-treated groups. The analgesic-treated groups were injected with nalbuphine (0.5, 1, 2, 4, and 5 mg/kg, subsequently, intrathecally) every alternate day for 14 days. These doses were selected according to the preliminary studies.
Nalufin (Nalbuphine HCl) was obtained as ampoules from Amoun Pharmaceutical Co. (S.A.E, Cairo, Egypt). All other chemicals were of high quality and were commercially available.
After 14 days of the experiment, the rats were killed by cervical dislocation 10 h after the last dose of nalbuphine injection. Their brains and spinal cords were removed. For the evaluation of histopathological changes in the cerebellum, a small section of tissue was immediately fixed with formalin. Thereafter, the specimens were embedded in paraffin, sectioned at 5 μm thickness, stained with hematoxylin and eosin, and examined by light microscopy.
Patients and methods
After obtaining approval from the local ethics committee of Minia University Hospital, the study was conducted on 30 children of either sex, aged between 6 and 10 years and suffering from ALL. Patients were excluded from the study if the platelet count was less than 100 000, there was prolonged bleeding and delayed clotting, of if there was infection at the site of injection. Patients with serum creatinine levels higher than 1.5 mg/dl were included in this study, whereas those levels higher than 7 mg/dl were excluded. All patients included in this study agreed to complete the study, including the follow-up.
The patient received the induction course of chemotherapy, which included vincristine, prednisone, doxorubicin, and the maintenance dose of chemotherapy, which included methotrexate and cyclosporine. These patients had mild renal impairment on the kidney function test and active HZ that presented with severe pain along the course of one of following dermatomes: L4, L5, S1, or S2, with the appearance of skin vesicles along the chin of the tibia and the back of the leg and thigh. These patients were planned to be treated with 20 mg/kg acyclovir orally four times daily for a period of 14 days , and with caudal injection of 5 mg nalbuphine HCl as an analgesic agent every alternate day for 14 days, with paracetamol administered orally at a dose of 7.5 mg/day in syrup form .
Full medical history taking and physical examination (chest, heart, abdomen, and other systems) were carried out. Preinjection investigation was performed to assess the platelet count, bleeding time, and clotting time to exclude the risk for bleeding tendency. In addition, the serum creatinine level was evaluated as an indicator of kidney function.
Caudal block was performed in a sterile operating theater as prescribed by Silvani et al. 
| Parameters assessed|| |
The following parameters were assessed.
Preinjection serum creatinine level
Preinjection and postinjection hemodynamic parameters assessed included heart rate, systolic blood pressure, and diastolic blood pressure.
Preinjection and postinjection assessment of pain severity
Pain severity was assessed on the basis of a Face Pain Scale (FPS) and a Behavioral Pain Assessment Scale, as our study was conducted on pediatric patients, some of whom were unable to provide a meaningful self-report of pain.
Face Pain Scale
This scale is suitable for patients 3 years or older. Pain was assessed by asking the child to point to the side of the face that best described the pain they were experiencing. The far left side of the face indicated 'no hurt', and the far right side of the face indicated 'hurts worse'.
Behavioral Pain Assessment Scale
In our study, the Behavioral Pain Assessment Scale was used with FPS in all patients to confirm the degree of pain. In this scale, the children's behavior in terms of facial expressions, restlessness, muscle tone, vocalization, and consolability was observed, and each was rated either 0, 1, or 2. These scores were added together to document the total pain score out of 10.
Preinjection and postinjection assessment of motor block by means of the Bromage score
The Bromage score was used to measure the degree of motor block in patients after caudal block and to rate it on a scale of 0-3.
All of the previous parameters were assessed before and 30 min after the end of the caudal injection, and the child returned to full consciousness from sevoflurane and the injection in the same manner every 48 h for 14 days.
Statistical analysis of the data
Results were expressed as mean ± SEM. One-way analysis of variance, followed by the Tukey-Kramar post-analysis test, was used to analyze the results for statistically significant differences. P-values less than 0.001 were considered significant. GraphPad Prism was used for statistical calculations (version 5.03 for Windows; GraphPad Software, San Diego California, USA; http://www.graphpad.com).
| Results|| |
Photomicrographs of the H&E-stained sections of the cerebellum of control rats showed normal histological features, with three well-organized cortical layers: the superficial molecular layer, the middle monolayer of Purkinje cells, and the dense layer of granular cells; the white matter was clearly visualized [Figure 1]a. In rats treated with nalbuphine at different doses (0.5, 1, 2, 4, and 5 mg/kg/day), sections of the cerebellar cortex showed no pathological changes compared with the control group [Figure 1]b. Photomicrographs of the H&E-stained sections of the spinal cords of control rats showed normal histological features of white and gray matter [Figure 2]a. Nalbuphine-treated rats showed no pathological changes as compared with the control group [Figure 2]b.
|Figure 1: (a) Histopathological changes in the H&E-stained sections of the cerebellum of rats from the saline-treated group, from left to the right: 1, molecular layer; 2, Purkinje cell layer; 3, white matter; 4, granular cell layer (×200). (b) Histopathological changes in the H&E-stained sections of the cerebellum of rats from the nalbuphine-treated groups, from left to the right: 1, molecular layer; 2, Purkinje cell layer; 3, white matter; 4, granular cell layer (×400). H&E, hematoxylin and eosin.|
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|Figure 2: (a) Histopathological changes in the H&E-stained sections of the spinal cords of rats from the saline-treated group, from left to the right: 1, white matter; 2, grey matter; 3, neurons (cell body); 4, ependymal canal (´400). (b) Histopathological changes in the H&E-stained sections of spinal cords from the nalbuphine-treated groups, from left to the right: 1, white matter; 2, grey matter; 3, neurons (cell body); 4, ependymal canal (×200). H&E, hematoxylin a nd eosin.|
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Analgesic effect of nalbuphine assessed on the basis of the Face Pain Scale
Preinjection Face Pain Scale
As regards preinjection pain assessment using the FPS, there was an insignificant decrease in the severity of pain on the third day as compared with the first day; however, there was a significant change in the severity of pain on days 5, 7, 9, 11, and 13 as compared with the first or third day [Figure 3]a.
|Figure 3: (a, b) Effect of nalbuphine on preinjection and postinjection FPS. Data represent mean ± SE. (a) Significant changes from the first day. FPS, Facial Pa in Scale.|
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Postinjection Face Pain Scale
A significant decrease in postinjection pain, as assessed by the FPS, was observed starting on the third day, and it continued to decreased significantly until the13th day of the study [Figure 3]b.
Analgesic effect of nalbuphine assessed on the basis of the Behavioral Pain Assessment Scale
There was a significant decrease in both preinjection and postinjection pain, as detected by BPS, starting from the third day, and it continued to decrease significantly until the 13th day [Figure 4]a and b.
|Figure 4: (a, b) Effect of nalbuphine on preinjection and postinjection BPS. Data represent mean ± SE. (a) Significant changes from the first day.|
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Motor effect of nalbuphine assessed by the Bromage score
As regards motor block assessment, there was no significant change in Bromage score between precaudal and postcaudal injections of nalbuphine.
Effect of nalbuphine on hemodynamic parameters
There were no significant changes in hemodynamic parameters, as shown in [Table 1].
Effect of nalbuphine on the plasma creatinine leve
There was insignificant changes in plasma creatinine level in patients received nalbuphine caudal, as shown in [Table 2].
| Discussion|| |
Our study included 30 patients with ALL who had renal impairment and acute HZ infection as complications. ALL is a cancer that affects the white blood cells. These cells fight infection and help protect the body against disease. Patients with ALL have too many immature white blood cells in their bone marrow. Without enough normal white blood cells, the body cannot fight infection .
Our patients received remission chemotherapy regimens in the form of vincristine, prednisone, and doxorubicin, followed by consolidation chemotherapy in the form of methotrexate and 6-mercaptopurine and cerebrospinal radiation.
Renal impairment is one of the complications that can occur in ALL patients in form of glomerular disease as membrane proliferative glomerulonephritis, with leukemic infiltration into the kidney, or with renal impairment as a side effect of chemotherapy .
In addition, HZ is frequently seen to occur in immunocompromised patients, especially in those with ALL receiving chemotherapy. Many studies have suggested that 25-30% of ALL patients receiving chemotherapy develop acute HZ during primary chemotherapy, which results in severe pain and may also be complicated by visceral dissemination .
Acute herpetic infection in those patients requires proper treatment to avoid systemic spread of infection and to relieve pain; the treatment regimen consists of antiviral therapy with adequate analgesia .
Acyclovir significantly shortens the time required for cutaneous healing. It can be administered either intravenously (which requires isolation of the patient in the hospital and involves high cost) or orally at 20 mg/kg/day in four divided doses, as administered in our study .
Furthermore, these patients require adequate analgesia in the form of NSAIDs, and one of the complications of NSAIDs is acute prerenal injury that occurs in malignant patients receiving chemotherapy. A variety of renal diseases and electrolyte disturbances can also result in a side effect, and NSAIDs can produce prerenal injury through IL2, which results in capillary leak syndrome and in turn leads to a decrease in effective circulation .
In our study, patients were suffering from asymptomatic renal impairment, as indicated by the kidney function test (serum creatinine ranged from 1.5 to 2 mg/dl), and had a higher tendency to use NSAIDs as analgesic agents.
Our study evaluated the efficacy of nalbuphine injected caudally every alternate day, in association with 7.5 mg/kg/day of paracetamol in three divided doses between caudal injections, in yielding an analgesic effect.
Nalbuphine is a partial agonist-antagonist opioid that acts as an agonist against k-receptors. Several studies have demonstrated that regionally applied k-agonists alone can produce useful analgesia through suppression of the pain transmission pathway .
k-Opioid receptors are distributed throughout the brain and spinal cord areas involved in nociception. The greatest concentrations of k-receptors in the nociceptive regions are in laminae I and II of Rexed in the spinal cord dorsal horn, as well as in the spinal nucleus of the trigeminal nerve (substantia gelatinosa) .
Nalbuphine acts primarily at the level of the first synapse in the nociceptive system in producing analgesia. k-Opioid receptors exist in the afferent neurons having cell bodies in the dorsal horn of the spinal cord. Moreover, nalbuphine acts on k-receptors existing in the afferent neurons of dorsal horn cells, which are considered the main site of activation of the varicella zoster virus. This may explain the adequate analgesic effect detected in our study .
Significant analgesic effect was observed immediately after caudal injection of nalbuphine, and statistically the best analgesic effect was observed on the ninth day of the study (after five injections), as detected by VAS (9.13 ± 0.1 on the first day vs. 3.62 ± 0.2 on the ninth day) and BPS (9.03 ± 0.1 6 on the first day vs. 1.5 ± 0.31 on the ninth day). This analgesic effect was obvious without motor block, as detected by the Bromage score. This means that caudal nalbuphine provides an adequate analgesia within a short time with insignificant changes in hemodynamic parameters. Moreover shorting the duration of analgesia and avoiding the use of NSAIDs prevents progressive impairment of renal function in those patients who already suffer from renal impairment, as detected by assessment of the serum creatinine level, which showed no significant change.
We planned to administer nalbuphine caudally in our study, as Eisenach et al.  suggested that nalbuphine on intravenous injection poorly penetrates the central nervous system.
Regional anesthesia (caudal) for children are growing in popularity as a route of analgesia because it has less disadvantage than other route of analgesia .
In our study we planned to inject nalbuphine caudally. The epidural space is rich in adipose tissue, in which the caudally administered nalbuphine spreads. This adipose tissue acts as a reservoir for drugs, which explains the prolonged analgesic effect of nalbuphine. Further, this method obviates the use of a catheter and the consequent risk for infection .
However, there is no danger associated with treating patients with renal impairment with nalbuphine, as many studies have suggested that nalbuphine undergoes hepatic metabolism to pharmacologically inactive conjugates. Both the unchanged drug and the conjugates are secreted into bile. The major route of elimination is fecal, with little renal elimination of either the unaltered drug or its metabolites .
Further, no pathological changes were observed in the cerebellum or spinal cord tissues of rats treated with nalbuphine at different doses as compared with control rats. These data are supported by the studies by Culebras et al.  and Fournier et al. , who suggested that intrathecal nalbuphine does not produce any histopathological change associated with the mixed agonist-antagonist butorphanol, and nalbuphine has been used intrathecally in humans without any reported neurotoxic side effects.
In addition, our study also experimentally evaluated the safety of nalbuphine on the neural tissues of rats. In the proposed study, we selected the cerebellar region of the rat brain, as the cerebellum is known to be critically concerned with muscular coordination and it smoothens the motor activity. In addition, nearly 50% of all neurons of the brain are located in this region, which occupies only 10% of the total brain volume and receives nearly 200 million afferent fibers. As the cerebellum is involved in fine coordination and control of voluntary movement, it may be vulnerable to injury .
| Conclusion|| |
Caudal injection of nalbuphine provided an adequate analgesic effect, without any apparent motor block, within a short duration in patients with ALL who were suffering from acute herpetic pain with mild renal impairment and were receiving a remission and consolidation course of chemotherapy.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]