Introduction

1

INTRODUCTION

Pain is an unpleasant sensory and emotional experience associated with actual or

potential tissue damage or defined in terms of such damage; it is a subjective experience

concerning a complex interaction of physiological, cultural, and environmental impacts. (1)

The value of combining local anaesthetics and opioids for postoperative pain relief

has been well established. The combination allows for a reduction in doses of both classes

of drugs, as a consequence lessening the likelihood of side effects attributable to each. (2, 3)

The use of the opioid mixed agonist-antagonist Nalbuphine as an analgesic agent

provides a number of benefits. Used as the sole opioid analgesic, it can cover mild to

moderate discomfort with a low prevalence of side effects. The ceiling effect of

Nalbuphine, which prevents it from providing sufficient analgesia to cover the most

intense pain, also prevents increasing sedation and respiratory depression as the dose is

increased, potentially supplying an extended safety margin in comparison to µ-agonists

.(4)

Pain Physiology

Pathways of Pain: (Figure 1)

Nociceptors, or pain receptors, are free nerve endings responding to painful stimuli.

Nociceptors are found in all tissues except articular cartridge, visceral pleura, lung

parenchyma, pericardium, brain and cord tissue; they transmit information to the brain.

They are stimulated by biological, electrical, thermal, mechanical, and chemical stimuli.

Pain perception happens when these stimuli are transmitted to the spinal cord and then to

the central regions of the brain. Pain impulses transmitted to the dorsal horn of the spine,

where they synapse with dorsal horn neurons inside the substantia gelatinosa after which

ascend to the brain. The main sensation of pain takes place at the thalamus. It continues to

the limbic system (emotional center) and the cerebral cortex, at which pain is perceived

and interpreted.

Two types of fibers are concerned in pain transmission. The large A delta fibers

cause sharp well-defined pain, called “fast or first pain", typically stimulated by a wound,

Introduction

2

an electrical shock, or a physical blow. Transmission through the A fibers is so rapid that

the body’s reflexes can actually respond earlier than the pain stimulus, resulting in

withdrawal of the affected body part even before the person perceives the pain stimulus.

After this fast pain, the smaller C fibers transmit dull burning or aching sensations, called

“second pain.” The C fibers transmit pain less rapidly than the A fibers do due to the fact

the C fibers are smaller and shortage a myelin sheath. The C fibers are the ones that cause

constant pain. In keeping with the gate control theory, stimulation of the fibers that

transmit non painful stimuli can block pain impulses at the gate within the dorsal horn. (5)

Pain mediator:

Pain perception occurs when tissue damage stimulates the free nerve endings called

pain receptors or the more specific name nociceptors. These receptors are present in all

peripheral nerves. Pain receptors are concentrated in the skin surface, soft tissue, artery

walls, muscle fibers, joint surface and periosteum. Pain receptors are lacked in most

internal organs like the lungs and uterus. Tissue damage can happen physically, with heat,

cold, stretch, pressure, spasm, or when blood supply is limited to certain tissue areas

causing damage known as ischemia. Also, the body releases substances produced by cell

damage like bradykinin and prostaglandins. Bradykinin is one of the most powerful pain

stimulating substances and it rapidly breaks down, for this it is found especially in acute

pain. Other types of chemicals involved in the physiology of pain include acetylcholine,

adenosine triphosphate, serotonin, histamine, potassium, leukotriene and substance P. (6, 7)

Introduction

3

Figure (1): An anatomical overview of pain pathways(8)

Spinal Anaesthesia

History:

Spinal analgesia was first introduced in 1885 but not used in clinical practice until

1899, when August Bier subjected himself to a clinical experiment in which he observed

anaesthetic impact and the typical side effect of post dural puncture headache. Within a

few years, spinal analgesia became widely used for surgical anaesthesia and was approved

as a safe and effective technique. Despite new drugs are used today, the original technique

has otherwise modified very little over many decades. (9)

Functional anatomy of spinal blockade: (Figure 2)

The vertebral column includes 33 vertebrae: 7 cervical, 12 thoracic, 5 lumbar, 5

sacral, and 4 coccygeal segments. The vertebral column contains three curves. The cervical

and lumbar curves are convex anteriorly, and the thoracic curve is convex posteriorly. Five

Introduction

4

ligaments bind the spinal column together. The supraspinous ligaments connect the apices

of the spinous processes from the seventh cervical vertebra (C7) to the sacrum. In the area

above C7, the supraspinous ligament is known as the ligamentum nuchae. The interspinous

ligaments hold the spinous processes together. The ligamentum flavum binds the laminae

above and below together. Finally, the posterior and anterior longitudinal ligaments

connect the vertebral bodies together.

Figure (2): The vertebral column and the common features of the vertebrae.(10)

The three membranes that surround the spinal cord are the dura mater, arachnoid

mater, and pia mater. The dura mater is the outermost layer. The dural sac extends to the

second sacral vertebra (S2). The arachnoid mater is the middle layer, and the subdural

space lies between the dura and arachnoid mater. The arachnoid mater also ends at the

second sacral vertebra (S2) like the dural sac. The pia mater clings to the spinal cord and

ends into filum terminale which helps to attach the spinal cord to the sacrum. The space

between the arachnoid and pia mater is called the subarachnoid space and spinal nerves run

in this space as well as CSF.

Introduction

5

Spinal nerves in the cervical area are named according to the upper cervical vertebral

body from which they exit. However, the eighth cervical nerve exits from the lower border

of the seventh cervical vertebral body, and this method of naming continues in the thoracic

and lumbar areas. The spinal nerve roots and spinal cord serve as the target for spinal

analgesia. (11)

Figure (3): Coverings of the spinal cord.(12)

Surface anatomy:

When preparing for spinal analgesic blockade, it is crucial to locate landmarks on the

patient. The iliac crests usually mark the interspace between the fourth and fifth lumbar

vertebrae, and a line can be drawn between them to assist locate this interspace. Care must

be taken to feel for the soft area between the spinous processes to find the interspace.

Depending on the level of analgesia necessary for the surgery and the ability to feel for the

interspace, the L3-4 interspace or the L4-5 interspace can be located to introduce the spinal

needle. Because the spinal cord ends at the L1 to L2 level, it would not be wise to attempt

Introduction

6

spinal analgesia at or above this level, although there is publication of higher level spinal

anesthesia. . (13)

It would be incomplete to discuss surface anatomy without mentioning the

dermatomes that are crucial for spinal analgesia. A dermatome is an area of skin innervated

by sensory fibers from a single spinal nerve. The tenth thoracic (T10) dermatome

corresponds to the umbilicus, the sixth thoracic (T6) dermatome: the xiphoid, and the

fourth thoracic (T4) dermatome: the nipple. (14)

Complications:

Complications of spinal blockade include local anaesthetic neurotoxicity and

neurologic injury, post dural puncture headache, high spinal blockade, and cardiovascular

collapse. (15)

Local Anaesthetics (LAs)

Local anaesthetics block sensory and motor function by preventing the permeability

of neuronal cell membranes to sodium. This action impedes the rapid influx of sodium

during the depolarization phase of the action potential and its onward transmission. Local

anaesthetics also exert their pharmacological actions through other ions such as calcium

and potassium. (16,17)

Make it produce a reversible block in nerve conduction when applied

locally to the nerve in appropriate concentration. (18)

Classification of LAs

1- Aminoesters

These agents possess an ester linkage (CO) between aromatic portion and

intermediate chain, they include:

A- Benzoic acid esters: e.g. Buacaine, Cocaine, Benzocaine and Tetracaine.

B- Para-aminobenzoic acid esters: Procaine, Chloroprocaine and Ravocaine.

C- Meta-aminobenzoic acid esters: Uncaine and Primacaine.(19)

Introduction

7

2- Aminoamides

They possess an amide linkage between the aromatic portion and intermediate chain,

they include: Lidocaine, Bupivacaine, Mepivacaine, Prilocaine and Ropivacaine. (20)

Figure (4): Classification of LAs (19)

Bupivacaine hydrochloride

Local anesthesia was in a major disaster till the evolvement of modern organic

chemistry that results in the synthesis of pure cocaine in 1891. New amino ester local

anesthetics were manufactured between 1891 and 1930, like benzocaine, procaine and

tetracaine. Also, amino amide local anesthetics were synthesized between 1898 and 1972

which contain bupivacaine, cinchocaine, mepivacaine, lidocaine, prilocaine, and

etidocaine.

Bupivacaine is of special importance because of its long duration of action and

history of clinical application. Synthesized in 1957, the introduction of bupivacaine on the

market in 1965. (21)

It is used by injecting it into the area, around a nerve that supplies the area, or into

the spinal canal's epidural space. It is available mixed with a tiny amount of epinephrine to

make it last longer.(18)

It typically begins working within 5 minutes when injected

intrathecaly and lasts for 3 to 4 hours. (22,23)

Physiochemical structure:

Bupivacaine is an anilide, 1-n- butyl DL piperidine-2- carboxylic acid 2-3 dimethyl

anilide HCL. Its molecule weights 302; Pka with 8.1, partition coefficient 560 and protein

bind percentage 95%. It combined the properties of reasonable onset, lengthy duration of

Introduction

8

action, strong conduction blockade and evident separation of sensory anaesthesia and

motor blockade. Bupivacaine is used in concentrations of 0.125%, 0.25%, 0.5% and 0.75%

for various regional anaesthetic procedures, including infiltration, peripheral nerve blocks,

extradural and spinal analgesia. (24)

Figure (5): Chemical structure of bupivacaine hydrochloride (25)

.

Pharmacokinetic properties:

Absorption:

The rate of absorption of bupivacaine and other local anaesthetics hangs on the dose

and concentration of drug given, the route of administration, the blood supply of the

administration site, and the presence or absence of epinephrine in the mixture.(26)

The average duration of action of bupivacaine varies approximately from three to

four hours (26).

Its most lengthy duration of action occurs when major peripheral never

blocks such as brachial plexus block are performed. In these cases, the mean duration of

action of 10 to 12 hours has been reported. (27)

Distribution:

Distribution of bupivacaine and other used local anaesthetics after systemic

absorption depends on the organ blood flow, the partition coefficient of local anaesthetic

between compartments and protein binding.

Organs that are richly perfused, such as the heart and brain, have higher drug

concentration (28)

Introduction

9

Metabolism and excretion:

The normal pathways for metabolism of bupivacaine may include aromatic

hydroxylation, N-dealkylation and amide hydrolysis conjugation. The urinary excretion of

it is dealkylation and hydroxylation metabolites which account for more than 40%of the

total anaesthetic dose administered. (29)

Duration of action:

The duration following spinal injection is about 210 to 240 minutes. The time of two

segments regression following epidural administration is approximately 2.5 hours. (22)

Mode of action

Bupivacaine binds to the intracellular portion of voltage gated sodium channels and

blocks sodium influx into nerve cells, which prevents depolarization. In the absence

depolarization, neither initiation nor conduction of a pain signal can occur. (16)

Medical uses

Bupivacaine is indicated for local infiltration, peripheral nerve block, sympathetic

nerve block, and epidural and caudal blocks. It is sometimes used in combination

with epinephrine to prevent systemic absorption and extend the length of time of action.

The 0.75% (most concentrated) formulation is used in retro bulbar block.(30)

It is the most

frequently used local anaesthetic in epidural anaesthesia during labor, besides

postoperative pain management.(31)

Contraindications

Bupivacaine is contraindicated in patients with known allergy reactions to

bupivacaine or amino-amide anaesthetics. It is also contraindicated in obstetrical

paracervical blockade and I.V regional anaesthesia (Bier block) because of possible risk of

tourniquet failure and systemic absorption of the drug and resulting cardiac arrest. The

0.75% formulation is contraindicated in epidural anaesthesia during labor because of the

relation to refractory cardiac arrest.(30)

Introduction

10

Adverse reactions:

Because block of voltage gated channel affects action potential propagation through

the body; it's not surprising that local anaesthetics have the ability for systemic toxicity. (16)

CNS adverse effects:

Typically happen at lower blood plasma concentrations including circumoral

numbness, facial numbness, vertigo, tinnitus, restlessness, anxiety, dizziness, fits, coma.

Initially, cortical inhibitory pathways are selectively suppressed leading to symptoms of

neuronal excitation. At higher plasma concentrations, both inhibitory and excitatory

pathways are suppressed, causing CNS depression and eventually coma.(30)

Cardiovascular adverse effects:

Bupivacaine seems to be much more cardiotoxic than other drugs, because it is more

potent and has high lipid solubility and a high protein binding form. It can produce sino-

atrial suppression leading to nodal and ventricular arrhythmias at levels far below detected

for CNS toxicity (serum ratio of CVS: CNS toxicity is 4:1). Despite the fact that

bupivacaine is 4 times more potent than lidocaine, however it is 16 times more cardiotoxic.

The cardiotoxicity is due mainly to block of cardiac muscles sodium channels.(24)

Intravenous infusion of a 20% lipid emulsion (eg, Intralipid 20%) has become an

accepted part of management for systemic toxicity from local anesthetics, and mainly

cardiac arrest that is resistant to standard therapy. (32)

Additives to local anaesthesia:

Vasoconstrictors have been mixed with local anaesthetics, and both Epinephrine and

Phenylephrine have been tried. Anaesthesia is augmented and prolonged with smaller

doses of local anaesthetics when Epinephrine or Phenylephrine is given. Tissue

vasoconstriction is produced, thus decreasing the systemic reabsorption of the local

anaesthetic and lengthening the duration of action by keeping the local anaesthetic in

relation to the nerve fibers. (33)

Alpha-2-adrenergic agonists can be mixed with spinal injections of local anaesthetics

in order to augment pain relief and prolong sensory blockade and motor block. (34)

Sensory

Introduction

11

block is thought to be mediated by either presynaptic or postsynaptic mechanisms.

Clonidine leads to hyperpolarization at the ventral horn of the spinal cord and potentiate

the action of the local anaesthetic, thus lengthening motor block when used as an adjuvant.

However, when used solo in intrathecal injections, Clonidine does not cause motor

blockade or weakness. (35)

Acetyl cholinesterase inhibitors hinder the breakdown of acetylcholine and produce

analgesia when given intrathecally. The pain relieving effects are due to increased

acetylcholine and generation of nitric oxide. (36, 37)

Many opioids, like Morphine, Fentanyl, Meperidine, Sufentanil, Nalbuphine, and

heroin have been given intrathecally for post-caesarean section analgesia. (38)

Opioids in spinal analgesia

Opioid Receptors: (Table 1)

Opioids combine to specific opioid receptors in the nervous system and other tissues.

There are three principal types of opioid receptors, μ, κ, and δ (mu, kappa, and delta). In

addition, there are also three subtypes of μ-receptor: μ1 and μ2, and the recently discovered

μ3. Another receptor of clinical significance is the opioid-receptor-like receptor 1 (ORL1),

which is participated in pain responses as well as having a major role in the development

of resistance to μ-opioid agonists used as analgesics.

The pharmacodynamic reaction to an opioid depends on the receptor to which it

binds, its affinity for this receptor, and rather the opioid is an agonist or an antagonist. For

example, the supraspinal analgesic characteristics of the opioid agonist morphine are

mediated by activation of the μ1 receptor; respiratory inhibition and physical dependence

by the μ2 receptor; and sedation and spinal analgesia by the κ receptor. Every group of

opioid receptors elicits a specific set of neurological reactions, with the receptor subtypes

(such as μ1 and μ2 for example) providing even more measurably specific reactions.

specific to each opioid is its distinct binding affinity to the different classes of opioid

receptors (e.g. the μ, κ, and δ opioid receptors are activated at variable magnitudes

according to the specific receptor binding affinities of the opioid). For example, the opiate

Introduction

12

alkaloid morphine shows high-affinity binding to the μ-opioid receptor, while Nalbuphine

shows high affinity to ĸ receptors. (39.40.41).

Table (1): Four major subtypes of opioid receptors. (42, 43)

Receptor Receptor REReceptor Subtypes Location Function

delta (δ)

OP1

δ1, δ2

brain

o pontine nuclei

o amygdala

o olfactory bulbs

o deep cortex

peripheral sensory nerves

analgesia

antidepressant

effects

physical dependence

kappa (κ)

OP2 κ1, κ2, κ3 brain

o hypothalamus

o periaqueductal gray

o claustrum

spinal cord

o substantia gelatinosa

peripheral sensory nerves

analgesia

sedation

miosis

inhibition of ADH

release

dysphoria

mu (μ)

OP3

μ1, μ2, μ3 brain

o cortex (laminae III and

IV)

o thalamus

o striosomes

o periaqueductal gray

spinal cord

o substantia gelatinosa

peripheral sensory nerves

intestinal tract

μ1:

analgesia

physical dependence

μ2:

respiratory

depression

miosis

euphoria

reduced GI motility

physical dependence

μ3:

Unknown

Nociceptin

receptors

OP4

ORL brain

o cortex

o amygdala

o hippocampus

o septal nuclei

o habenula

o hypothalamus

spinal cord

Anxiety

depression

appetite

development of

tolerance to μ

agonists

Introduction

13

Mechanism of action of intrathecal opioids:

Opioids injected in the subarachnoid space seem to act mainly on µ receptors in the

substantia gelatinosa of the dorsal horn by inhibiting excitatory neuropeptide release from

C fibers. The extent of uptake from the cerebrospinal fluid by the dorsal horn is determined

mainly by the physicochemical properties of the drug, and in specific, lipid solubility.

Lipid-soluble compounds enjoy larger direct diffusion into neural tissue besides greater

delivery to the dorsal horn by spinal segmental arteries. (44)

Taking of opioids into the systemic circulation after intrathecal administration is

usually not clinically significant, as the doses typically used in the spinal space are tiny.

This is mainly important to breast feeding women and is an extra advantage of neuraxial

modes of post caesarean section pain management as compared with the larger doses of

opioids needed systemically. (45, 46)

Complications and drawbacks of intrathecal opioids:

1. Neurotoxicity: Clinicians should exercise caution before injecting any agent into the

epidural or subarachnoid space; the potential for irritation or outright damage to neural

structures always must be considered. Preservative-free opioids (which is

commercially available for epidural and intrathecal administration) has no deleterious

effect on neural tissue.(47)

2. Sensory Changes: Intrathecal opioids block the afferent messages from A-delta and C

fibers to reach spinal cord but that efferent nerve impulses are unaffected. These

sensory changes can be clinically significant, especially when they extend to the

cervical dermatomes. In such cases, patients may feel that they can't breathe or

swallow; this can be quite distressing. These patients must be reassured those

respiratory efforts are not impaired and that these symptoms will subside in thirty to

sixty minutes.(48,49)

3. Hypotension: many studies have described a decline in blood pressure after intrathecal

opioid administration in pregnant women. Initially some investigators concluded that

intrathecal opioids exerted a local anaesthetic effect, which resulted in a

sympathectomy. (50)

However, subsequent studies have shown that the decreased blood

Introduction

14

pressure results from pain relief rather than from a sympathectomy. However,

sympathetic blockade can be resulted if either a local anaesthetic or clonidine is

administered intrathecally with the opioid.(51,52)

4. Nausea and Vomiting: It is hard to determine the incidence of nausea and vomiting as

a direct drawback of epidural and intrathecal opioid administration. Other causes of

nausea and vomiting include pain, and systemic opioids, which are often given before

intrathecal or epidural opioids. The cause of nausea mediated by neuraxial opioid

administration is unknown, but it may be caused by the affection of afferent input at

the chemoreceptor trigger zone or at the nucleus of the tractus solitarius, which is a key

relay site in the visceral sensory network. Of interest is that nausea is less common

after epidural or intrathecal opioid injection during labour than after the injection of

the same drugs for post caesarean pain relief. Although the incidence of nausea is low,

treatment must be available.(53,54)

5. Pruritus: Pruritus is the most frequent side effect of epidural or intrathecal opioid

administration.(55,56)

Intrathecal opioid administration seems to be related to a higher

incidence of itching than epidural opioid administration (41.4% versus 1.3%).(57)

Two

options to decline the incidence of pruritus are administration of a lower dose of

opioids (58)

and /or local anaesthetic.(59)

With epidural opioid injection, both the

incidence and degree of pruritus seem to be dose dependent. However, an even tinyl

dose of intrathecal opioids may result in evident pruritus.(60)

6. Respiratory Depression: The administration of opioids by any passage contains some

risk of respiratory inhibition. When administrating an opioid epidurally or

intrathecally, parameters that affect the risk of respiratory inhibition include the choice

of drug (and its pharmacokinetics), the dose, and its interaction with opioids and other

CNS depressants given intravenously. With intraspinal opioids, the most important

parameter affecting the onset of respiratory inhibition is the lipid solubility of the drug.

In general, if respiratory inhibition is going to happen, it will occur within two hours of

the administration of a lipid soluble opioid such as Fentanyl, Nalbuphine and

Sufentanil. When a lipid soluble opioids gain access to the CSF, they are quickly

absorbed by lipophilic body tissues. next clearance and elimination resemble those

associated with I.V injection of the same drug. Thus, with intraspinal injection of a

Introduction

15

lipid soluble opioid, the “time window” for respiratory inhibition is short. Conversely,

with a hydrophilic like morphine, the onset of respiratory inhibition is delayed. Once a

hydrophilic drug such as morphine reaches the CSF, it tends to stay in the CSF. Rostral

migration and absorption into the respiratory centers occur over many hours; thus

respiratory depression may not occur until six to twelve hours after injection of the

drug.

7. Urinary Retention: Urinary retention is a inconvenient side effect of neuraxial

opioids. The cause may be the rapid onset of detrusor muscle inhibition that results

from the sacral spinal action of opioids. The onset of urinary retention seems to

parallel the onset of analgesia. It is hard to determine the mass of this problem during

labour, because parturient often require urinary catheter for other reasons. (61)

8. Delayed Gastric Emptying: I.V or I.M opioid administration results in delayed

gastric emptying. Delayed gastric emptying can predispose a patient to nausea and

vomiting. Besides, it may result in a greater volume of gastric contents. (62, 63)

Nalbuphine hydrochloride

Structure: (Figure 3)

Nalbuphine is a synthetic opioid agonist-antagonist analgesic of the phenanthrene

series. It is chemically related to the widely used opioid antagonist, naloxone, and the

potent opioid analgesic, Oxymorphone. Chemically Nalbuphine hydrochloride is (17-

(cyclobutylmethyl)-4, 5α-epoxymorphinan-3, 6α, 14-triol hydrochloride). Nalbuphine

hydrochloride molecular weight is 393.91 and is soluble in H2O and ethanol (0.8%);

insoluble in CHCl3 and ether. Nalbuphine hydrochloride has pKa values of 8.71 and 9.96.

The molecular formula is C21H27NO4·HCl.

Nalbuphine is a sterile solution suitable for subcutaneous, intramuscular, or

intravenous injection. Contain 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous,

and 0.2% of a 9:1 mixture of methylparaben and propylparaben as preservatives; pH is

adjusted, if necessary to 3.5 to 3.7 with hydrochloric acid. Nalbuphine is also available in

ampoules in a sterile, paraben-free formulation.

Introduction

16

Figure (6): Chemical formula of Nalbuphine(64)

Mechanism of action:

Is an effective analgesic. Its analgesic potency is essentially the same as of morphine

on a milligram basis. Receptor studies exhibit that Nalbuphine binds to µ, κ, and δ

receptors, but not bind to sigma receptors. Nalbuphine is mainly κ agonist/partial µ

antagonist analgesic.

Nalbuphine by itself has effective opioid antagonist activity at doses equal to or lower

than its analgesic dose. When given following or along with µ agonist opioid analgesics (e.g.

morphine, oxymorphone, and fentanyl) it may partially reverse or block opioid resulting

respiratory depression from the µ agonist analgesic. It may share in withdrawal in patients

dependent on opioid drugs, so should be used cautiously in patients who have been given mu

opioid analgesics on a regular base. (65, 66)

Onset and Duration:

Onset of intravenous Nalbuphine is 2 to 3 min, onset of subcutaneous and I.M

Nalbuphine is less than 15 min. Duration of analgesic effect is three to six hr. The plasma

half-life of Nalbuphine is five hours.

Introduction

17

Dose and administration:

The usual suggested adult dose is ten mg for a 70 kg individual, given intravenously;

this dose may be repeated every three to six hours as needed. Dosage should be tailored

according to the intensity of the pain, physical status of the patient, and other drugs which

the patient may be receiving. In non-tolerant patients, the recommended single maximum

dose is 20 mg, with a maximum total 24 hours dose of 160 mg. (67, 68, 69)

Metabolism & catabolism:

When Nalbuphine is taken orally, it is not as effective for pain relief as when given

IM, mainly because of first-pass metabolism in gastrointestinal tract and liver. Tmax is 30

min (IM). Nalbuphine is not bound to plasma proteins and transfer the placenta.

Metabolized in the liver, approximately 7% eliminated in urine without change and in

feces. Plasma t 1/ 2 is 5 h. (70)

Adverse reactions:

The most frequent side effect in patients treated in clinical studies with Nalbuphine

was sedation (36%), less common reactions were: (sweaty, clammy 9%), (nausea,

vomiting 6%), (dizziness, vertigo 5%), (dry oral mucosa 4%), and (headache 3%).

Anaphylactic/anaphylactoid and other serious allergic reactions have been reported

following the use of Nalbuphine and may need immediate, supportive medical treatment.

These reactions could include shock, respiratory distress, respiratory depression,

bradycardia, cardiac arrest, hypotension, or laryngeal edema. Some of these allergic

hypersensitivity may be life-threatening. Other allergic-type reactions reported include

stridor, bronchospasm, wheezing, edema, rash, itching, nausea, vomiting, sweating,

weakness, and shakiness. (71)

Fentanyl

Fentanyl is short acting narcotic-analgesics with a potent morphine-like action and

structural relationship to meperidine and amileridine.

Introduction

18

Figure (7): Chemical structure of fentanyl. (72)

It's a white crystalline material with pH in the range of 4.05-7.0, soluble in both

water and 2.5% methyl alcohol, its melting point is in the range of 149-151°C and with a

chemical structure {(N-1-phenethyl-4-piperidinyl)-propionanilidine dihydrogen citrate}.(72)

Pharmacokinetics

When given in equipotent doses, fentanyl is more potent and has a less time of onset

and duration of action than either morphine or meperidine. It's highly lipophilic and is

rapidly absorbed from the epidural and other fatty spaces giving blood levels similar to the

intravenous route. It's excreted in the gastric mucosa and reabsorbed from the alkaline juice

from the small intestine undergoing enterohepatic circulation with rebound effects at 3-5

hours following injection. Fentanyl is mostly destroyed in the hepatic cells and about 10%

excreted by the kidney. It is metabolized to compounds without appreciable analgesic

activity. The initial reaction involves N-deakylation to produce nor-fentanyl. Both fentanyl

and nor fentanyl are metabolized further by hydroxylation to compounds which is excreted

in urine. (72)

Mode of action

Fentanyl combines to opiate receptors present in the CNS where it inhibits the

secretion of substance (P) the neurotransmitter of pain at first relay in the spinal cord.

Opiates interact with specific and saturable binding sites or receptors in brain and other

organs and these receptors are widely but unequally distributed throughout CNS. They are

present in highest concentration in the limbic system (frontal and temporal cortex, amygdale

and hippocampus), medial thalamus, posterior pituitary, hypothalamus, periaqueductal grey

matter of brain stem and substantia gelatinosa of spinal cord.

Introduction

19

Cerebral cortex has a lesser density of receptors and the cerebellum is devoid of these

receptors. Peripherally opiate receptors are located in gastrointestinal tract and there's a

suggestion of their presence in peripheral tissues possibly on sensory nerve endings. Different

types of opiate receptors have been classified: Mu (including Mu1 and Mu2), Kappa, Sigma,

Delta & Epsilon. The augmentation in the level of sensory analgesia associated with fentanyl

systemic administration can be due to enhancement of subclinical spinal analgesia by it. The

mechanism of enhancement of the spread of spinal analgesia after systemic opioid

administration is unknown. It may be due to changes in the pharmacokinetics or

pharmacodynamics of the intrathecal local anesthetic. (72-74)

Pharmacological action

Profound analgesia

Fentanyl is 50-100 times more effective than morphine as an analgesic, but a large

part of this difference is due to more lipophilicity rather than to increased affinity to the mu

receptors. It has a relatively shorter duration of action. The increased usage of the patient-

controlled analgesia and epidural infusions are related to an increased use of fentanyl. It

appears to cause less sedation than morphine. (72)

One hundred micrograms of fentanyl has the analgesic potency of 10 mg morphine

or 75 mg meperidine. (73)

Mode of action

Fentanyl is not similar to morphine and less potent narcotics, causes relatively little

inhibition of cortical activity. Fentanyl may produce symptoms and signs characteristic of

narcotic analgesic including euphoria, miosis, bradycardia and broncho-spasm with a peak

of action fifteen minutes after administration. (73)

Introduction

20

1- CNS

Fentanyl injection in normocapnic patient causes no change in the intracranial

pressure with a decline in the cerebral perfusion pressure from 60.4 mmHg to 47.8

mmHg.(74)

2- Cardiovascular system

Cardiovascular stability is recognized with the usage of fentanyl as it was reported

that there's no variation in blood pressure, pulse or stroke volume even when given in

moderately large doses because of the fact that it doesn't release histamine in human.

Fentanyl in small doses of 1 µg/kg was related to slight augment in the myocardial

blood flow and oxygen uptake, a decline in the coronary vascular resistance, unchanged

coronary oxygen saturation with depressed amount of lactate uptake. On the other side,

fentanyl in a large dose of 10 µg/kg produced a decline in myocardial blood flow and

oxygen uptake to below control level, with an augmentation in the coronary vascular

resistance, and production of tiny amount of lactate. (74)

3- Respiratory system

Fentanyl depresses all indices of respiratory function. Clinically used doses of

fentanyl produce a dose related respiratory depression, which is maximum at five minutes

after IV administration and may persist for up to three to four hours. change in respiratory

rate and alveolar ventilation, associated with fentanyl could last longer than the analgesic

action. As the dose of fentanyl is increased, the decline in the pulmonary exchange

becomes greater. Larger doses produce respiratory arrest.(72)

4-Gastrointestinal tract

PONV are clinically detected in using fentanyl; which is less in incidence in

comparison with that occurring with morphine and meperidine. (72)

5- Miosis

It's found in all patients receiving fentanyl.

Introduction

21

6- Muscular rigidity

Large doses may result in muscle rigidity in muscles of the thorax, abdomen and

extremities and thought to be due to CNS stimulation. During surgery the usage of muscle

relaxant adverse any muscle rigidity that fentanyl may produce.

7- Endocrinal and metabolic effect

Intravenous anaesthesia or the supplementation of inhalational anaesthesia with large

doses of fentanyl has been appeared to either attenuate or abolish the neuro-endocrine and

metabolic reaction to trauma of surgery.

Dose and passage of administration

The usual intravenous analgesic dose is one to two µg/kg body weight. The dose to

attenuate stress reaction during cardiac surgery is 50 µg/kg of fentanyl. The infusion dose

of fentanyl to prevent postoperative stress response is 4-10 µg/kg/h. (25)

Injection of a bolus of fentanyl two µg/kg to supplement the anesthetic induction,

significantly attenuate the pressor responses during laryngoscopy and intubation. In larger

doses of 5-6 µg/kg fentanyl completely abolishes these responses. Inclusion of 12.5-40 µg

fentanyl in the local anaesthetic mixture used for subarachnoid block provided 4-5 hours of

postoperative analgesia. (75)

The addition of fentanyl to low-dose intrathecal bupivacaine for C.S or day case

surgery has been widely accepted measure. It lengthens the duration of spinal analgesia

and lessen the amount of analgesic dose for postoperative pain.(74)

Antidote for fentanyl:

Naloxone, is a pure opioid antagonist. (76,77)

Naloxone is a medication used to counter

the actions of opioid especially in overdose. It will mainly reverse the depression of the

CNS, respiratory system, and hypotension. Naloxone is most frequently injected

intravenously for fastest action, which usually causes the drug to perform within a minute,

and last up to 45 minutes. It can also be given via intramuscular or subcutaneous injection.

Also, a wedge device (nasal atomizer) attached to a syringe can be used to create a mist

which delivers the drug to the olfactory mucosa. The individual is carefully monitored for

Introduction

22

signs of improvement in respiratory function and mental status. If minimal or no

improvement is observed within two to three minutes dosing may be repeated every two

minutes until the maximum dose of ten mg has been reached. If there is no response at this

time another diagnosis and treatment should be pursued. If patients do exhibit a response

they should remain under close observation as the effect naloxone may wear off before those

of the opioids and they may require repeat dosing at a later time. (78)

Aim of the Work

23

AIM OF THE WORK

This study was carried out to compare the effect of intrathecal nalbuphine versus

intrathecal fentanyl as adjuvants to bupivacaine, as regard the post-operative analgesia, the

hemodynamic stability, the onset of sensory/motor block and the duration of action in

patients undergoing internal fixation of tibia.

Patients

24

PATIENTS

This study was carried out in Elhadra University Hospital on fifty patients aged 20 –

50 years; belonging to American Society of Anaesthesiologists (ASA) physical status I or

II, scheduled for internal fixation of tibia of expected duration less than 3 h, under spinal

anaesthesia, patients were studied in a prospective and randomized way.

Exclusion criteria:

Patients with significant co-existing conditions such as hepatorenal and

cardiovascular diseases.

Patients with contraindications to regional anesthesia like local infection or

bleeding disorders.

Patients with allergy to opioids, long-term opioids use, and a history of chronic

pain.

Patients with extremes in weight or in length .

After approval from the local ethical committee, a written informed consent was

obtained from each patient.

Patients in the study were randomly classified into two equal groups using closed

envelope method.

Group F:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 1

ml fentanyl (50μg).

Group N:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus

1ml nalbuphine hydrochloride (1.6 mg); (20 mg Nalbuphine in 12 ml normal saline 0.9%).

The all above preparations were done under completely aseptic techniques.

Methods

25

METHODS

1. Preoperative preparations:

Medical history: history of previous spinal anaesthesia, cardiovascular diseases,

neurological diseases, spinal surgery or trauma, haematological diseases or long

term anticoagulant therapy.

Clinical examination: vital signs (blood pressure, pulse rate and temperature),

cardiovascular, respiratory and neurological examination and evaluation of the

lumbar spine for any pathological lesions.

Routine laboratory investigations: complete blood picture, fasting blood sugar,

blood urea, serum creatinine, Prothrombin time (PT), partial thromboplastin time

(PTT), Prothrombin activity and INR and any investigation according to the

patient condition.

Electrocardiogram (ECG) for all patients over 35 years of age.

Consent was taken from every patient following an explanation of the technique and

its possible complication.

* Patients were fasting for the previous 6 hours.

2. Anaesthetic technique:

Patients were monitored using standard monitoring (pulse oximetry,

electrocardiogram, noninvasive arterial blood pressure monitoring) using a multi channel

monitor. A baseline recording of the previous measurements was taken at 5 minutes before

starting the spinal anaesthesia. airway resuscitation equipments and all equipments for the

spinal blockade were readily available and ready for use, together with all necessary

medications were drawn up prior to positioning the patient for spinal analgesia.

Before the administration of neuroaxial anaesthesia, 18-gauge intravenous cannula

was inserted in the non-dominant hand and intravenous preload of 10 mL/kg lactated

Ringer’s solution was given, in 15 minutes, after which the intravenous infusion was

slowed to the minimum rate required to maintain vein patency.

Methods

26

Patient was placed in the sitting position; skin was prepared with betadine. At the

puncture site, 2 ml of 2% lidocaine were injected subcutaneously. The puncture was

performed at L3-4 interspace using a 25 gauge spinal needle (Quincke) by midline

approach. After a successful dural puncture, the anaesthetic solution was injected

according to the group. The patient was then turned supine immediately elevation of the

head by a pillow. Oxygen administered through a simple face mask (5 L/ min).

The total volume of the intrathecal anaesthetic was standardized at 3 ml and was

injected according to each group as follows:

Group F:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus 1

ml fentanyl (50μg).

Group N:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric bupivacaine plus

1ml nalbuphine hydrochloride (1.6 mg); (20 mg Nalbuphine in 12 ml normal saline 0.9%).

* The all above preparations were done under completely aseptic techniques.

Methods

27

Measurement

The following parameters were measured for each patient:

1. Demographic data:

Age (yrs), sex, weight (kg) and Height (cm).

2. Hemodynamic parameters:

Non-invasive mean arterial blood pressure (mmHg).

Heart rate (beats/minute).

These parameters were measured and recorded at 5 minutes before the intrathecal

injection and then at 2, 4, 6, 8, 10, minutes, and then every 15 minutes till the end of the

procedure .

3. Assessment of sensory blockade:

Sensory blockade: was determined by ice cold test tube to estimate the following:

Time (in minutes) of the onset of sensory block at T10 dermatome.

Time (in minutes) for 2 segment regression which was defined as the time it took

for the sensory level to decrease by 2 dermatomal levels measured from the highest

obtained sensory level every 15 min.

4. Assessment of the motor block:

Motor blockade: was evaluated by the (modified Bromage score) (79)

:

Time (in minutes) of onset of motor blockade from the end of intrathecal injection

till the patient reached complete motor blockade (modified Bromage score 3).

Duration of motor block (in minutes) was recorded from the time at which the

patient reached complete motor blockade (modified Bromage score 3) to the time

the patient was able to rise his/her legs in bed against gravity (modified Bromage

score 0) every 30 min in the post-operative care unit .

Methods

28

Table (2): Modified Bromage score.

Score Definition

0 Able to raise straightened legs against resistance, no detectable motor

block.

1 Unable to raise straightened legs, but able to flex knees.

2 Unable to flex knees, but able to flex ankle.

3 Unable to move hip, knee or ankle.

5. Post-operative analgesia:

a. Duration of analgesia:

- The duration of analgesia was defined as the period from spinal injection to the first

time when the patient complained of pain in the postoperative period.

- Patients was assessed using Visual analogue scale (VAS), in the immediate

postoperative period, then every 2hours for the first 8hours, then every 6hours for

the rest of the first 24hours.

Visual analogue scale (VAS)

Figure (8): Visual Analogue Scale

- It ranges from 0 indicating no pain till 10 indicating severe intolerable pain with

variable degrees of ascending pain in between.(80)

b. Postoperative analgesic requirements:

- The time of the first request analgesia was recorded and treated by intramuscular

diclofenac sodium (75mg) in a dose of 1mg/kg and repeated after 1 hour if needed

up to 2 ampoules.

- Paracetamol 1 g IV every 8 hours was given for analgesia to all patients starting

immediately postoperative (time zero).

Methods

29

- Total dose of analgesic requirements was calculated and elaborated statistically.

6. Complication:

Such as, hypotension, bradycardia, respiratory depression, pruritis, nausea, vomiting

and shivering were recorded.

- Hypotension will be defined as systolic blood pressure less than 90mmHg and\or a

decrease of more than 20% from baseline blood pressure(81,82)

.

- Bradycardia will be defined as HR<50 beat\min.

- Respiratory depression will be defined as respiratory rate <10 breath\min(83)

.

Methods

30

Statistical analysis of the data

Data were fed to the computer and analyzed using IBM SPSS software package

version 20.0. (Armonk, NY: IBM Corp) Qualitative data were described using number and

percent. The Kolmogorov-Smirnov test was used to verify the normality of distribution

Quantitative data were described using range (minimum and maximum), mean, standard

deviation and median. Significance of the obtained results was judged at the 5% level.

The used tests were

1 - Chi-square test

For categorical variables, to compare between different groups

2 - Fisher’s Exact or Monte Carlo correction

Correction for chi-square when more than 20% of the cells have expected count less

than 5

3 - Student t-test

For normally distributed quantitative variables, to compare between two studied

groups

Results

31

RESULTS

This study was carried out in Elhadra University Hospital on fifty

patients aged 20 – 50 years; belonging to American Society of

Anaesthesiologists (ASA) physical status I or II, scheduled for internal

fixation of tibia of expected duration less than 3 h, under spinal anaesthesia,

patients were studied in a prospective and randomized way.

Patients in the study were randomly classified into two equal groups

using closed envelope method.

Group F:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric

bupivacaine plus 1 ml fentanyl (50μg).

Group N:

Patients received intrathecal injection of 2 ml of 0.5% hyperbaric

bupivacaine plus 1ml nalbuphine hydrochloride (1.6 mg).

Demographic data (Table 1):

Age (years):

The mean age for the two studied groups F and N was 32.24±7.28 and 29.36±6.92

respectively. There were no statistical significant differences between the two studied

groups (P= 0.158).

Sex:

Group F included 13 males and 12 females, and group N included 14 males and 11

females. There were no statistical significant differences between the two studied groups

regarding sex (P= 0.777).

Results

32

Anthropometrics (Table 3):

Weight (kg):

The mean weight for the two studied groups F and N was 69.36±11.66 and

70.36±11.89 respectively. There were no statistical significant differences between the

studied groups (P= 0.765).

Height (cm):

The mean height for the two studied groups F and N was 160.76±7.53 and

161.96±9.42 respectively. There were no statistical significant differences between the

studied groups (P= 0.621).

Table (3): Comparison between the two studied groups according to demographic

data

F

(n = 25)

N

(n = 25) Test of

Sig. p

No. % No. %

Sex

Male 13 52.0 14 56.0 2=

0.0810.777

Female 12 48.0 11 44.0

Age (years)

Min. – Max. 20.0 – 49.0 21.0 – 47.0 t=1.434 0.158

Mean ± SD. 32.24 ± 7.28 29.36 ± 6.92

Height

Min. – Max. 152.0 – 179.0 152.0 – 182.0 t=0.497 0.621

Mean ± SD. 160.76 ± 7.53 161.96 ± 9.42

Weight

Min. – Max. 48.0 – 92.0 45.0 – 91.0 t=0.300 0.765

Mean ± SD. 69.36 ± 11.66 70.36 ± 11.89

2: Chi square test t: Student t-test

p: p value for comparing between the studied groups

Results

33

Figure (9): Comparison between the two studied groups according to sex

Figure (10): Comparison between the two studied groups according to age

Results

34

Figure (12): Comparison between the two studied groups according to height

Figure (13): Comparison between the two studied groups according to weight

Results

35

Duration of Surgery (minutes) (Table 4):

The mean duration of surgery for the two studied groups F and N was 54.40±8.21

and 54.80±12.29 respectively. There were no statistical significant differences between the

studied groups (P= 0.893).

Table (4): Comparison between the two studied groups according to duration of

operation (min)

Patient's No. Duration of operation (min)

F N

1 75 100

2 60 55

3 55 70

4 45 45

5 55 50

6 50 50

7 55 45

8 50 55

9 45 70

10 60 60

11 55 45

12 75 60

13 45 50

14 55 45

15 45 45

16 65 60

17 50 45

18 60 50

19 45 45

20 55 50

21 50 50

22 55 45

23 50 55

24 50 60

25 55 65

Min. 45.0 45.0

Max. 75.0 100.0

Mean 54.40 54.80

±SD. 8.21 12.29

t 0.135

p 0.893

t: Student t-test p: p value for comparing between the two groups

Results

36

Figure (13): Comparison between the two studied groups according to duration of

operation (min)

Results

37

Hemodynamic measurements:

1. Changes in the heart rate (beats/min). (Table 5a, 5b & 5c (

In group F:

Preoperatively, the mean value of the HR was 88.64 ± 12.12 beat/min. Intra-

operatively, it increased significantly to 90.64 ± 11.13 beat/min 2 minutes after intrathecal

injection, 94.92 ± 11.76 after 10 min and 92.56 ± 12.39beat/min after 25min.

In group N:

Preoperatively, the mean value of the HR was 87.88 ± 9.27 beat/min. Intra-

operatively, it decreased significantly at 2,6,8,40 and 55 minutes after intrathecal injection.

There were no significant changes in the HR throughout the times of measurement

between the two studied groups.

2. Changes in the MABP (mmHg). (Table 6a,6b & 6c (

In group F:

Preoperatively, the mean value of the MABP was 81.80 ± 7.59 mmHg. Intra-

operatively, it decreased significantly at 2,4,6, 8, 10, 25, and 40 minutes after intrathecal

injection, except at 55min it changed insignificantly to80.36 ± 6.38 mmHg.

In group N:

Preoperatively, the mean value of MABP was 86.04±11.02 mmHg. Intra-operatively,

it decreased significantly at 2, 4, 6, 8, 10, 25, and 40 minutes after intrathecal injection,

except at 55min it changed insignificantly to 85.08 ± 10.34mmHg.

There were no significant changes in the MABP throughout the times of

measurement between the two studied groups.

Results

38

Table (5a): Changes in Heart rate (beats/min) in group F

Patient's

No.

Heart rate (beats/min)

5 min

Before

After

2 min 4 min 6 min 8 min 10 min 25 min 40 min 55 min

1 65 68 65 66 66 71 65 64 60

2 100 93 86 92 99 102 108 100 94

3 85 90 88 82 83 99 99 92 89

4 90 94 104 109 114 110 106 100 95

5 60 64 65 73 63 65 61 60 60

6 88 90 88 84 81 85 83 84 80

7 77 79 75 76 79 83 81 76 70

8 88 90 90 90 89 92 89 84 84

9 78 80 77 80 82 85 82 78 76

10 75 77 74 75 78 82 75 71 70

11 90 93 90 92 87 96 92 88 85

12 88 89 87 88 93 107 98 88 82

13 100 103 102 106 103 105 99 92 90

14 98 99 105 107 100 102 94 93 94

15 95 97 94 97 100 102 90 90 88

16 92 95 90 86 89 90 91 87 85

17 80 87 89 93 103 113 105 98 91

18 95 97 87 84 87 92 90 87 84

19 112 108 105 108 104 103 101 98 98

20 110 112 115 101 99 100 98 86 85

21 96 102 97 99 94 97 97 90 88

22 93 90 83 89 94 110 108 111 105

23 80 85 83 84 86 96 100 98 97

24 87 88 85 82 79 92 99 94 91

25 94 96 90 91 90 94 103 98 96

Min. 60.0 64.0 65.0 66.0 63.0 65.0 61.0 60.0 60.0

Max. 112.0 112.0 115.0 109.0 114.0 113.0 108.0 111.0 105.0

Mean 88.64 90.64 88.56 89.36 89.68 94.92 92.56 88.28 85.48

±SD. 12.12 11.13 12.07 11.42 11.96 11.76 12.39 11.63 11.25

t 3.333* 0.067 0.501 0.632 3.298 2.093 0.186 1.792

p 0.003*

0.947 0.621 0.533 0.003*

0.047*

0.854 0.086

t: Paired t-test

p: p value for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

Results

39

Table (5b): Changes in Heart rate (beats/min) in group N

Patient's

No.

Heart rate (beats/min)

5 min

Before

After

2 min 4 min 6 min 8 min 10 min 25 min 40 min 55 min

1 90 88 89 82 80 91 90 89 92

2 91 87 89 87 84 92 91 90 87

3 100 96 98 94 92 101 95 93 94

4 93 90 92 87 89 95 90 85 90

5 82 78 81 80 82 80 78 75 85

6 85 82 84 82 84 88 86 81 87

7 86 82 85 81 83 83 82 76 90

8 80 76 81 79 82 81 78 82 78

9 101 99 108 102 105 110 102 94 92

10 72 70 74 73 67 74 72 67 66

11 92 86 89 87 89 86 85 93 85

12 89 88 90 89 90 91 89 90 85

13 83 82 84 77 78 86 85 87 82

14 75 72 74 69 70 76 74 78 76

15 110 107 109 107 102 109 107 104 105

16 94 93 101 97 94 106 100 97 92

17 81 81 83 77 79 83 82 80 79

18 77 75 77 72 75 77 76 80 76

19 85 83 85 80 79 86 84 81 83

20 79 77 79 73 77 79 77 72 73

21 86 86 92 82 85 100 94 85 87

22 93 94 100 87 89 109 101 90 92

23 85 83 84 79 81 87 80 78 79

24 83 82 84 77 78 84 83 80 81

25 105 102 104 97 92 101 99 96 100

Min. 72.0 70.0 74.0 69.0 67.0 74.0 72.0 67.0 66.0

Max. 110.0 107.0 109.0 107.0 105.0 110.0 107.0 104.0 105.0

Mean 87.88 85.56 88.64 83.88 84.24 90.20 87.20 84.92 85.44

±SD. 9.27 9.18 9.87 9.60 8.84 10.93 9.56 8.70 8.60

t 7.371* 1.295 6.963

* 4.754

* 2.223

* 0.883 3.477

* 3.610

*

p <0.001*

0.208 <0.001* <0.001

* 0.036

* 0.386 0.002

* 0.001

*

t: Paired t-test

p: p value for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

Results

40

Table (5c): Comparison between the two studied groups according to heart rate

(beats/min)

Heart rate

(beats/min)

F(n = 25) N(n = 25) t p

Mean ± SD. p5min. Mean ± SD. p5min.

5 min before 88.64 ± 12.12 87.88 ± 9.27 0.249 0.804

After

2 min 90.64 ± 11.13 0.003* 85.56 ± 9.18 <0.001

* 1.760 0.085

4 min 88.56±12.07 0.947 88.64 ± 9.87 0.208 0.026 0.980

6 min 89.36± 11.42 0.621 83.88 ±9.60 <0.001* 1.836 0.073

8 min 89.68 ± 11.96 0.533 84.24 ± 8.84 <0.001* 1.829 0.074

10 min 94.92 ± 11.76 0.003* 90.20 ± 10.93 0.036

* 1.470 0.148

25 min 92.56 ± 12.39 0.047* 87.20 ± 9.56 0.386 1.713 0.093

40 min 88.28 ± 11.63 0.854 84.92 ± 8.70 0.002* 1.156 0.253

55 min 85.48 ± 11.25 0.086 85.44 ± 8.60 0.001* 0.014 0.989

Data was expressed by using mean ± SD. t: Student t-test

p: p value for comparing between the two groups

p5min.: p value for Paired t-test for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

5 m

in b

efo

re

Aft

er

2 m

in

Aft

er

4 m

in

Aft

er

6 m

in

Aft

er

8 m

in

Aft

er

10 m

in

Aft

er

25 m

in

Aft

er

40 m

in

Aft

er

55 m

in

0.0

75

80

85

90

95

100

He

art

ra

te (

be

ats

/min

)

F N

Figure (14): Comparison between the two studied groups according to heart rate

(beats/min)

Results

41

Table (6a): Changes in mean arterial blood pressure in group F

Patient's

No.

Mean arterial blood pressure (mmHg)

5 min

Before

After

2 min 4 min 6 min 8 min 10 min 25 min 40 min 55 min

1 80 77 75 72 75 82 82 78 81

2 88 85 80 74 72 67 68 71 78

3 82 75 72 70 73 77 80 75 80

4 77 75 70 65 60 63 66 71 78

5 65 62 60 57 67 68 70 73 75

6 82 80 75 76 77 80 83 84 86

7 85 80 79 77 75 79 82 87 88

8 90 92 88 86 86 83 89 90 84

9 92 90 91 88 87 85 88 94 93

10 84 82 82 80 77 76 83 86 86

11 86 84 82 80 76 76 80 79 82

12 78 76 77 75 72 70 74 76 80

13 75 72 71 68 66 66 72 73 77

14 74 72 68 65 66 69 72 72 76

15 83 80 80 73 68 66 71 80 85

16 86 83 80 79 77 78 83 85 85

17 84 80 73 68 65 63 70 72 80

18 100 95 90 92 91 88 85 83 83

19 78 75 70 72 68 65 67 71 75

20 92 84 98 96 88 91 90 92 90

21 83 75 77 70 68 69 74 75 78

22 78 75 71 68 66 62 59 67 71

23 73 75 65 63 60 60 57 59 63

24 80 77 71 66 63 61 68 78 81

25 70 75 72 70 68 66 69 71 74

Min. 65.0 62.0 60.0 57.0 60.0 60.0 57.0 59.0 63.0

Max. 100.0 95.0 98.0 96.0 91.0 91.0 90.0 94.0 93.0

Mean 81.80 79.04 76.68 74.0 72.44 72.40 75.28 77.68 80.36

±SD. 7.59 7.0 8.66 9.26 8.56 9.03 9.07 8.36 6.38

t 4.847* 6.514

* 8.544

* 8.953

* 7.126

* 4.759

* 3.236

* 1.278

p <0.001*

<0.001* <0.001

* <0.001

* <0.001

* <0.001

* 0.004

* 0.214

t: Paired t-test

p: p value for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

Results

42

Table (6b): Changes in mean arterial blood pressure in group N

Patient's

No.

Mean arterial blood pressure (mmHg)

5 min

Before

After

2 min 4 min 6 min 8 min 10 min 25 min 40 min 55 min

1 82 80 78 80 75 79 75 80 83

2 67 64 62 53 55 56 55 58 60

3 87 82 77 80 78 75 78 80 81

4 79 78 78 81 77 75 81 78 82

5 75 73 70 72 74 74 77 80 78

6 91 86 83 97 71 82 80 82 83

7 96 93 91 85 80 75 82 80 86

8 95 88 86 82 77 76 75 81 80

9 84 87 80 72 65 66 69 73 77

10 99 94 94 90 92 90 93 95 100

11 103 97 96 93 90 91 92 94 99

12 78 73 72 68 67 70 80 78 80

13 87 86 87 83 82 84 90 89 91

14 77 75 76 74 75 76 78 82 83

15 81 82 78 76 76 74 83 80 82

16 93 95 84 75 70 72 76 80 85

17 69 70 69 66 65 68 71 75 77

18 102 93 96 92 91 94 97 100 102

19 75 76 76 75 73 71 78 78 80

20 72 75 74 72 70 73 76 77 78

21 79 72 72 69 66 62 64 67 72

22 94 87 85 78 81 82 87 89 92

23 85 86 84 82 81 83 86 90 92

24 94 92 95 92 90 93 97 95 101

25 107 103 100 97 95 96 93 100 103

Min. 67.0 64.0 62.0 53.0 55.0 56.0 55.0 58.0 60.0

Max. 107.0 103.0 100.0 97.0 95.0 96.0 97.0 100.0 103.0

Mean 86.04 83.48 81.72 79.36 76.64 77.48 80.52 82.44 85.08

±SD. 11.02 9.76 9.77 10.52 9.81 10.06 10.08 9.82 10.34

t 3.760* 6.015

* 5.614

* 7.311

* 6.333

* 3.538

* 2.654

* 0.763

p 0.001*

<0.001*

<0.001* <0.001

* <0.001

* 0.002

* 0.014

* 0.453

t: Paired t-test

p: p value for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

Results

43

Table (6c): Comparison between the two studied groups according to mean arterial

blood pressure (mmHg)

Mean arterial blood

pressure (mmHg)

F (n = 25) N (n = 25) t p

Mean ± SD p5min Mean ± SD p5min

5 min before 81.80 ± 7.59 86.04±11.02 1.584 0.121

After

2 min 79.04 ± 7.0 <0.001* 83.48 ± 9.76 0.001

* 1.457 0.152

4 min 76.68 ± 8.66 <0.001* 81.72 ± 9.77 <0.001

* 1.930 0.060

6 min 74.0 ± 9.26 <0.001* 79.36±10.52 <0.001

* 1.912 0.062

8 min 72.44 ± 8.56 <0.001* 76.64±9.81 <0.001

* 1.613 0.113

10 min 72.40 ± 9.03 <0.001* 77.48 ± 10.06 <0.001

* 1.879 0.066

25 min 75.28 ± 9.07 <0.001* 80.52 ± 10.08 0.002

* 1.933 0.059

40 min 77.68 ± 8.36 0.004* 82.44±9.82 0.014

* 1.845 0.071

55 min 80.36 ± 6.38 0.214 85.08 ± 10.34 0.453 1.943 0.059

Data was expressed by using mean ± SD. t: Student t-test

p: p value for comparing between the two groups

p5min.: p value for Paired t-test for comparison between 5 min Before and each other periods

*: Statistically significant at p ≤ 0.05

5 m

in b

efo

re

Aft

er

2 m

in

Aft

er

4 m

in

Aft

er

6 m

in

Aft

er

8 m

in

Aft

er

10 m

in

Aft

er

25 m

in

Aft

er

40 m

in

Aft

er

55 m

in

0

65

70

75

80

85

90

Me

an

art

eri

al b

loo

d p

ressure

(m

mH

g)

F N

Figure (15): Comparison between the two studied groups according to mean arterial

blood pressure (mmHg)

Results

44

Sensory block:

1. Time of the onset of sensory block (minutes): Table (7)

In group F, the onset of sensory block ranged between 1.20 and 2.35 min, with a mean of

1.65±0.25 min. While in group N, it ranged between 1.48 and 2.0 minutes with mean of 1.64±0.11

min.

Comparison between the two studied groups showed that there was no statistical

significant difference between the two groups as regard onset of sensory block (p=0.855)

2. Time for two-segment regression (minutes): Table (8)

In group F, time for two-segment regression ranged between 110 and 145 min, with a mean

of 124±8.51 min. While in group N, it ranged between 117 and 131 minutes with mean of

124.18±4.82 min.

Comparison between the two studied groups showed that there was no statistical

significant difference between the two groups as regard time for two-segment regression

(p=0.927)

Results

45

Table (7): Comparison between the two studied groups according to time of the

onset of sensory block (minutes)

Patient's No. Time of the onset of sensory block (minutes)

F N

1 1.80 2

2 1.20 1.65

3 1.50 1.55

4 1.6 1.48

5 1.57 1.53

6 1.58 1.71

7 1.55 1.66

8 1.7 1.65

9 1.55 1.52

10 1.55 1.60

11 1.62 1.63

12 1.70 1.67

13 1.60 1.69

14 1.55 1.49

15 1.62 1.56

16 1.55 1.73

17 1.71 1.68

18 2 1.67

19 2.30 1.54

20 2.35 1.59

21 1.50 1.70

22 1.35 1.70

23 1.65 1.69

24 1.53 1.68

25 1.57 1.58

Min. 1.20 1.48

Max. 2.35 2.0

Mean 1.65 1.64

±SD. 0.25 0.11

t 0.185

p 0.855

t: Student t-test p: p value for comparing between the two groups

Results

46

Figure (16): Comparison between the two studied groups according to time of the onset

of sensory block (minutes)

Results

47

Table (8): Comparison between the two studied groups according to time for two-

segment regression (minutes)

Patient's No. Time for two-segment regression (minutes)

F N

1 118 119

2 115 129

3 127 122.5

4 120 125

5 122 119

6 117 118

7 128 130

8 130 129

9 127 127

10 118 122

11 115 127

12 124 131

13 127 117

14 115 119

15 122 129

16 118 120

17 128 130

18 145 129

19 120 128

20 140 125

21 110 126

22 140 128

23 126 119

24 119 117

25 129 119

Min. 110.0 117.0

Max. 145.0 131.0

Mean 124.0 124.18

±SD. 8.51 4.82

t 0.092

p 0.927

t: Student t-test p: p value for comparing between the two groups

Results

48

Figure (17): Comparison between the two studied groups according to time for two-

segment regression (minutes)

Results

49

Motor block:

1. Onset of motor blockade (minutes): Table (9)

In group F, the onset of motor blockade ranged between 4.0 and 6.0 min, with a mean of

5.25±0.44 min. While in group N, it ranged between 4.9 and 6.0 minutes with mean of 5.59±0.26

min.

Comparison between the two studied groups showed that there was statistical

significant difference between the two groups as regard earlier onset of motor blockade in

group F when compared with group N (p=0.001*)

2. Duration of motor blockade (minutes): Table (10)

In group F, the duration of motor blockade ranged between 100 and 160 min, with a mean of

129.28±15.34 min. While in group N, it ranged between 120 and 131 minutes with mean of

126.16±3.77 min.

Comparison between the two studied groups showed that there was no statistical

significant difference between the two groups as regard duration of motor blockade

(p=0.332)

Results

50

Table (9): Comparison between the two studied groups according to onset of the

motor blockade (minutes)

Patient's No. Onset of the motor blockade (minutes)

F N`

1 5 4.90

2 4.50 5.66

3 4.90 5.30

4 5.30 5.66

5 5.2 5.73

6 5.5 5.55

7 5.30 5.40

8 5.70 5.69

9 5.20 5.57

10 6 5.20

11 5.22 5.85

12 5 5.32

13 5.80 5.80

14 5.30 5.26

15 5.40 5.69

16 5.25 6

17 5.80 5.73

18 4 5.78

19 5 5.57

20 5 5.62

21 5.30 5.35

22 5.35 5.84

23 6 5.77

24 5 5.79

25 5.25 5.83

Min. 4.0 4.90

Max. 6.0 6.0

Mean 5.25 5.59

±SD. 0.44 0.26

t 3.388*

p 0.001*

t: Student t-test p: p value for comparing between the two groups

Results

51

Figure (18): Comparison between the two studied groups according to onset of the motor

blockade (minutes)

Results

52

Table (10): Comparison between the two studied groups according to duration of

motor blockade (minutes)

Patient's No. Duration of motor blockade (minutes)

F N`

1 140 130

2 110 122

3 132 125

4 125 127

5 128 130

6 112 122

7 143 131

8 150 128

9 145 129

10 126 120

11 135 125

12 110 130

13 105 120

14 130 123

15 125 128

16 107 122

17 140 131

18 130 130

19 134 129

20 125 127

21 100 128

22 160 130

23 145 123

24 130 120

25 145 124

Min. 100.0 120.0

Max. 160.0 131.0

Mean 129.28 126.16

±SD. 15.34 3.77

t 0.987

p 0.332

t: Student t-test p: p value for comparing between the two groups

Results

53

Figure (19): Comparison between the two studied groups according to duration of motor

blockade (minutes)

Results

54

Postoperative analgesia:

1. Duration of analgesia(minutes): Table (11)

In group F, the duration of analgesia ranged between 120 and 187 minutes with a

mean of 155.60±24.26. While in group N, it ranged between 155 and 182 minutes with

mean of 171.44±8.21.

Comparison between the two studied groups showed that there was a statistical

significant longer duration of analgesia in group N when compared with group F,

(p=0.004*).

2. Time for 1st rescue analgesia(minutes): Table (12)

In group F, the timing of first rescue analgesia ranged between 193 and 252 minutes

with a mean of 228.40±20.63. While in group N, it ranged between 216 and 247 minutes

with mean of 236.48±8.74.

Comparison between the two studied groups showed that there was no statistical

significant differences between the two groups as regards timing of first rescue analgesia,

(p=0.081).

3. Total dose of analgesic requirements(mg): Table (13)

In group F the total amount of rescue analgesia with diclofenac sodium (75mg)

ranged between 75.0 and 150 with a mean of 93.0±32.69 mg, while in group N it ranged

between 75.0 and 150 with a mean of 87.0±28.06 mg. There was no significant difference

between the two groups a regards the total amount of diclofenac sodium consumed, (p=

0.484)

Results

55

Table (1): Comparison between the two studied groups according to duration of

analgesia (minutes)

Patient's No. Duration of analgesia (minutes)

F N

1 180 181

2 130 170

3 150 175

4 160 163

5 176 179

6 122 160

7 185 169

8 185 178

9 180 182

10 150 177

11 125 159

12 125 158

13 140 167

14 187 171

15 170 178

16 130 173

17 170 180

18 130 155

19 162 165

20 120 174

21 125 180

22 170 182

23 185 168

24 150 177

25 183 165

Min. 120.0 155.0

Max. 187.0 182.0

Mean 155.60 171.44

±SD. 24.26 8.21

t 3.092*

p 0.004*

t: Student t-test p: p value for comparing between the two groups

Results

56

Figure (20): Comparison between the two studied groups according to duration of

analgesia (minutes)

Results

57

Table (12): Comparison between the two studied groups according to time for 1st

rescue analgesia (minutes)

Patient's No. Time for 1

st rescue analgesia (minutes)

F N

1 250 240

2 195 236

3 200 241

4 230 230

5 242 245

6 199 233

7 252 238

8 249 243

9 244 247

10 220 238

11 215 220

12 223 224

13 247 232

14 251 244

15 238 247

16 198 240

17 243 246

18 206 216

19 233 235

20 193 241

21 209 239

22 240 246

23 250 239

24 235 230

25 248 222

Min. 193.0 216.0

Max. 252.0 247.0

Mean 228.40 236.48

±SD. 20.63 8.74

t 1.803

p 0.081

t: Student t-test p: p value for comparing between the two groups

Results

58

Figure (21): Comparison between the two studied groups according to time for 1st rescue

analgesia (minutes)

Results

59

Table (13): Comparison between the two studied groups according to total dose of

analgesic consumption of diclofenac sodium (75mg)

Patient's No.

Total dose of analgesic consumption of

diclofenac sodium (75mg)

F N

1 75 75

2 75 150

3 75 75

4 75 75

5 75 150

6 75 75

7 150 75

8 75 75

9 75 75

10 75 75

11 150 75

12 150 75

13 75 75

14 75 75

15 75 150

16 75 75

17 75 150

18 75 75

19 150 75

20 75 75

21 75 75

22 150 75

23 75 75

24 75 75

25 150 75

Min. 75.0 75.0

Max. 150.0 150.0

Mean 93.0 87.0

±SD. 32.69 28.06

Median 75.0 75.0

U 287.5

p 0.484

U: Mann Whitney test

p: p value for comparing between the two groups

Results

60

Figure (22): Comparison between the two studied groups according to total dose of

analgesic consumption of diclofenac sodium (75mg)

Results

61

Complication:

In group F 28% of cases developed hypotension, 12% developed nausea and

vomiting, 16% developed pruritus and 8% of cases developed shivering.

In group N 20% of cases developed hypotension, 8% developed nausea and

vomiting, 8% developed pruritus and 4% of cases developed shivering.

No cases developed bradycardia or respiratory depression.

There were no statistical significant differences between the two studied groups

regarding complication.

Table (14): Comparison between the two studied groups according to complications

Complications F

(n = 25)

N

(n = 25) χ

2 p

Hypotension 7(28.0%) 5(20.0%) 0.439 0.508

Nausea and vomiting 3(12.0%) 2(8.0%) 0.222 FE

p=1.000

Pruritis 4(16.0%) 2(8.0%) 0.758 FE

p=0.667

Shivering 2(8.0%) 1(4.0%) 0.355 FE

p=1.000

Bradycardia 0(0.0%) 0(0.0%) – –

Respiratory depression 0(0.0%) 0(0.0%) – –

2: Chi square test FE: Fisher Exact

p: p value for comparing between the two groups

Figure (23): Comparison between the two studied groups according to complications.

Discussion

62

DISCUSSION

Tibial shaft fracture is considered the most common long bone fracture in orthopedic

practice. Fixation with intramedullary nail has commonly been used and validated to be

efficient (84)

. Pain in the knee is the most common complication after tibial nailing. Its

occurrence has been documented from 10 to 86% of the cases, especially in young and

active patients. (85,86)

So it's important to choose an efficient analgesic regimen with least side‐effects to

allow timely mobility, perfect functional recovery and to avoid postoperative morbidity

and mortality.

Spinal anesthesia is a trusted technique for lower limb surgeries. It is simple to

perform and offers fast onset and effective sensory and motor block. Bupivacaine

hydrochloride is a frequently used local anesthetic in spinal anesthesia. Although, the

duration of spinal analgesia by bupivacaine is limited and it has many drawbacks as

well.(87)

When opioids given Intrathecally segmental analgesia occurs when opioids bind to

opioid receptors in the dorsal horn of the spinal cord. They prolong the time of analgesia

and permit early ambulation of patients due to their sympathetic and motor nerve sparing

activities when given intrathecally.(88)

In the present study intrathecal opioids were used in relatively high doses to prolong

time of post-operative analgesia as an option of opioid free postoperative analgesia, to

minimize the requirement for postoperative analgesics and to avoid adverse effects of

systemic administrated opioids.

Fentanyl is a lipophilic μ-receptor agonist exerts its action by binding with opioid

receptors in the dorsal horn of spinal cord and also have a supraspinal spread and action.(89)

Nalbuphine is a highly lipid soluble opioid with activity that suggests an agonist

action at the κ opioid receptors and activity as an antagonist at the µ-opioid receptor. (90,91)

Nalbuphine and other κ agonists have provided reasonably potent analgesia in certain

Discussion

63

models of visceral nociception. There have been a few studies of varying quality that have

supported the utility of neuraxially given Nalbuphine in managing postoperative pain. (92)

Intrathecal nalbuphine and fentanyl were studied with low doses of nalbuphine (0.8

mg) and fentanyl (25 μg). This study compared higher doses of nalbuphine and fentanyl to

know the efficacy and occurrence of side effects. (93).

This study was conducted in Al-Hadara university Hospital on fifty patients aged 20

– 50 years; American Society of Anaesthesiologists (ASA) physical status I or II,

scheduled for internal fixation of tibia of expected duration less than 3 h, under spinal

anaesthesia, patients were studied in a prospective and randomized way.

There were no significant differences in the heart rate (HR) and mean arterial blood

pressure (MABP) between the two studied groups throughout all times of measurement.

In agreement with the present study , Jyothi et al. (94)

used three doses of intrathecal

nalbuphine 0.8, 1.6, and 2.5 mg on patients undergoing lower abdominal or lower limb

orthopedic surgeries , he concluded that using of nalbuphine hydrochloride with

bupivacaine doesn't cause gross hemodynamic disturbances even with increasing the dose

from 0.8 to 2.4 mg. Same results were found by Naaz et al. (95)

who conducted a study on

90 patients undergoing lower limb orthopedic surgery under spinal block, using two

different doses of nalbuphine 0.8 mg or 1.6 mg versus 25 μg of fentanyl, it was concluded

that there was no significant difference regarding spinal block characteristics and

haemodynamic parameters.

Gaiser et al. (96)

carried a study to compare the time of analgesia and occurrence of

side effects of three doses of intrathecal fentanyl (25 μg, 37.5 μg, 50 μg) with three doses

of intrathecal sufentanil (5 μg, 10 μg, 15 μg) on 60 ASA I and II patients in active labor

who wanted analgesia, All spinal injections were followed by a drop in BP, There was no

significant difference between the groups regarding the percent decrease in systolic (SBP)

or diastolic blood pressure (DBP).also, There was no significant change in HR.

Regarding characteristics of sensory and motor blockage there was no statistically

significant difference between group F and group N as regard the onset time of sensory

Discussion

64

block, Time for two-segment regression and duration of motor blockage all over the time

of the present study.

On the other hand, the onset time of complete motor block was more rapid with

fentanyl (mean 5.25±0.44 min) than nalbuphine (mean 5.59±0.26 min) and this was

statistically significant (p=0.001*), this may be clarified by the high lipid solubility and

rapid tissue uptake of fentanyl over nalbuphine.

Our result was in agreement with the study performed by Gomaa et al. (93)

, where

sixty female patients of ASA grades I and II scheduled for elective cesarean deliveries

under spinal anesthesia were randomly distributed into 2 equal groups; Group F: received

intrathecal injection of 2 ml of bupivacaine plus fentanyl (25 μg); Group N: received

intrathecal injection of 2 ml of bupivacaine nalbuphine (0.8 mg) ,no variances were found

between both groups as regards the start of sensory block, 2 segment regression of sensory

block and duration of motor block, but earlier onset of motor block in fentanyl group when

compared to nalbuphine group.

This study revealed that the period of analgesia was significantly longer in group

N(mean 171.44±8.21min) when compared with group F(mean 155.60±24.26min),

(p=0.004*), although there was no major differences between group N(mean

236.48±8.74min) and group F (mean 228.40±20.63) as regard timing of first rescue

analgesia, (p=0.081). And as regards the total amount of diclofenac sodium consumed,

group N (mean 87.0±28.06mg) and group F (mean 93.0±32.69mg), (p= 0.484).

Naaz et al (95)

compared the analgesic efficacy of fentanyl (group F: 25 μg) with that

of two doses of nalbuphine (group NL: 0.8 mg and group NH:1.6 mg) when compined

with bupivacaine heavy in spinal anaesthesia, the study revealed that The duration of

analgesia was significantly extended in the nalbuphine group when compared with fentanyl

group.

Mukherjee et al. (97)

formulated a study on one hundred patients, aged 20–60 years,

scheduled for elective lower limb orthopedic surgeries to conclude whether nalbuphine

elongate post-operative analgesia by comparing three doses of intrathecal nalbuphine 0.2,

0.4 and 0.8mg with control and to find out the ideal dose which prolonged analgesia

without increased side effects. It was observed that lengthiest duration of postoperative

Discussion

65

analgesia was in the group in which 0.8 mg nalbuphine was used as an adjuvant as

compared to minor doses of nalbuphine.

Borah et al. (98)

, performed a comparative study to assess the effect of different doses

of intrathecal nalbuphine (0.4, 0.8 and 1.6 mg) as adjuvant to ropivacaine in elective lower

limb surgeries, it was observed that the time of analgesia was maximum with 1.6 mg

nalbuphine followed by 0.8 mg then 0.4mg.

Gupta et al. (99)

. studied intrathecal nalbuphine against intrathecal fentanyl as an

additive with bupivacaine for orthopedic operation of lower limbs, patients of fentanyl

group were given 25 μg of fentanyl +17.5 mg of hyperbaric bupivacaine and patients of

nalbuphine group were given 2 mg of nalbuphine +17.5 mg of hyperbaric bupivacaine, The

entire duration of analgesia in patients of nalbuphine group was significantly longer when

compared with fentanyl group, but on contrary to the present study They found out that the

duration of rescue analgesia was much more prolonged when 2 mg of nalbuphine was

given intrathecally as compared to 25 μg of fentanyl, This significantly prolong duration of

rescue analgesia.

Ahmed et al. (100)

.evaluated the potentiating action of intrathecal nalbuphine with

bupivacaine in the scope of postoperative analgesia in patients scheduled for elective total

abdominal hysterectomy under subarachnoid block, three doses of nalbuphine were studied

(0.8, 1.6, and 2.4 mg), The total duration of analgesia was longer with 1.6mg group when

compared to 0.8 mg group, and 2.4mg group, They found out that the mixture of

intrathecal bupivacaine with nalbuphine significantly elongated postoperative analgesia as

compared to control group and a 1.6 mg dose showed the best results.

Regarding complication, there was no major difference between the two groups, in

current study 7 cases (28.0%) in group F developed hypotension, 2 cases (8.0%) developed

shivering and 3 cases (12.0%) reported nausea and vomiting, while in group N 5 cases

(20.0%) developed hypotension, only 1 case (4.0%)developed shivering and 2 cases

(8.0%) reported nausea and vomiting. there was no hypotension present excluding it as a

cause of nausea and vomiting.

Discussion

66

Pruritus was observed in 4 cases (16.0%) of group F and in 2 cases (8.0%) of group

N. Respiratory depression and bradycardia were not described in the two studied groups all

over the study time.

Mostafa et al. (101)

compared the analgesic effects and period of analgesia in addition

to the side effects of 50 mg tramadol and 2 mg nalbuphine administered via the IT route

for postoperative pain control after transurethral resection tumor of the bladder. No major

postoperative complications like respiratory depression, neurological sequelae or

complaints were observed among the two groups. The frequency of hemodynamic side

effects as decreased blood pressure, bradycardia and respiratory depression were

minimum. They concluded that, intrathecal injection of 50 mg tramadol and intrathecal 2

mg nalbuphine when given with 0.5% bupivacaine had a comparable postoperative

analgesia in the patients without creating significant related side effects like nausea,

vomiting, pruritis and respiratory depression.

The same results was shown by Jyothi et al. (94)

who studied the outcome of three

doses of intrathecal nalbuphine hydrochloride with bupivacaine (either intrathecal 15 mg

of bupivacaine + 0.5 mL normal saline or 15 mg of bupivacaine with either of nalbuphine

0.8, 1.6, and 2.5 mg + 0.5 mL normal saline) for lower abdominal and orthopedic and

concluded that adverse effects like nausea, vomiting, urinary retention and shivering were

statistically insignificant.

The same was documented by Gutstein et al (102)

in a study following ‘‘major

gynecological surgeries’’ in patients who were given intrathecal Nalbuphine plus

Bupivacaine as there was no prevalence of postoperative nausea and vomiting. Nausea and

vomiting which occurred after the administration of opioid analgesics are believed to be

due to stimulation of chemoreceptor trigger zone in the area postrema of the lower

brainstem. Since this effect seems to be µ-receptor-mediated, so Nalbuphine may not seem

to result in postoperative nausea or vomiting. In contrast to the present study Gutstein

demonstrated that Nalbuphine does not produce pruritus even at doses sufficient to cover

abdominal surgical pain. They presumed that the lack of µ-receptor agonist activity as well

as absence of histamine release was the cause. Further, the µ-antagonist property of

Nalbuphine can be used to treat µ-receptor-mediated pruritus generated by µ-opioid

agonists.

Summary

67

SUMMARY

The effective relief of pain is a paramount importance for patients undergoing

surgery. This should be achieved for humanitarian reasons, but there is now evidence that

pain relief has significant physiological effects. Not only does effective pain relief means a

smoother postoperative course with earlier discharge from hospital, but it may also reduce

the onset of chronic pain syndromes.

The simplicity of the technique of spinal anaesthesia and its reliability has made it

one of the preferred techniques in lower limb surgery. Unexpected early regression of

spinal block or prolonged operation can cause intraoperative pain. Increasing the dose of

local anesthetics, addition of opioids to local anesthetics for spinal anesthesia would be

helpful for prolonging the spinal blockade and maintaining prolonged postoperative

analgesia.

The aim of the present work was to compare the effect of nalbuphine versus fentanyl

as adjuvants to intrathecal bupivacaine, as regard the post-operative analgesia, the

hemodynamic stability, the onset of sensory/motor block and the duration of action in

patients undergoing internal fixation of tibia.

The present study was carried out on 50 ASA I or II patients scheduled for internal

fixation of tibia under spinal analgesia, categorized into two groups:

Group: F Patients received intrathecal injection of 2 ml of 0.5% hyperbaric

bupivacaine plus 1 ml fentanyl (50μg).

Group: N Patients received intrathecal injection of 2 ml of 0.5% hyperbaric

bupivacaine plus 1ml nalbuphine hydrochloride (1.6 mg).

Preoperative evaluation was done by complete history taking, physical examination

and necessary laboratory investigations.

Before starting the spinal anaesthesia basic monitoring was applied to the patients

including electrocardiogram (ECG), noninvasive blood pressure and pulse oxymetry.

Baseline readings were measured before starting spinal anaesthesia.

Summary

68

Patients received a volume preload in the form of 10 mL/kg lactated Ringer’s

solution, within 15 minutes, then they were placed in the sitting position and midline

puncture was performed at L3-4 interspace using a 25 gauge spinal needle, After injection,

the patient lied supine with the head resting on a pillow. Oxygen by nasal cannula was

given at 5 L/min throughout the procedure.

Measurements

1) Demographic data: Age (yrs), sex, weight (kg) and Height (cm)

2) Hemodynamic parameters: heart rate (beats/min), mean arterial blood pressure

(mmHg), was recorded as base line at 5 minutes before the intrathecal injection

and then at 2, 4, 6, 8, 10, minutes, and then every 15 minutes till the end of the

procedure.

3) Assessment of sensation: Time (in minutes) of the onset of sensory block at T10

dermatome, Time for 2 segment regression every 15 min determined by ice cold

test.

4) Assessment of motor function: Time (in minutes) of onset of motor blockade

from the end of intrathecal injection till the patient reached complete motor blockade

(modified Bromage score 3), Duration of motor block was recorded from the time at

which the patient reached complete motor blockade (modified Bromage score 3) to

the time the patient was able to rise his/her legs in bed against gravity (modified

Bromage score 0) every 30 min

5) Side effects: Incidence of peri-operative side effects including (hypotension,

bradycardia, respiratory depression, pruritis, shivering, nausea and vomiting) will be

noted.

6) Postoperative analgesia: duration of analgesia using visual analogue scale (VAS)

in the immediate postoperative period, then every 2hours for the first 8hours, then

every 6hours for the rest of the first 24hours, The time of the first request analgesia.

7) Total dose of IM diclofenac sodium was calculated.

Summary

69

The result of the present study showed that:

There was no statistically significant difference between the two studied groups as

regards age, weight, height and duration of surgery.

In the two groups mean arterial blood pressure significantly decreased after spinal

analgesia, but there was no significant difference between the two groups as

regard heart rate and mean arterial pressure all over the study time.

There was no significant difference between the two groups as regard onset,

duration of sensory block and duration of motor block all over the study time.

Onset of motor block was significantly earlier in group F than group N

Duration of analgesia was significantly longer in group N when compared with

group F

There was no significant difference in time of the 1st request analgesia and total

dose of diclofenac sodium between the two groups.

In the two studied groups there was no cases experienced respiratory depression

or bradycardia.

As regard hypotension, shivering, pruritus, nausea and vomiting showed no

significant difference between the two studied groups all over the study time

Conclusion

70

CONCLUSION

From the present study, the following can be concluded:

1. Spinal analgesia plays an important role providing satisfying opioid free

postoperative analgesia.

2. The addition of intrathecal Nalbuphine 1.6 mg to spinal bupivacaine (0.5%

hyperbaric solution) prolonged the onset time of motor blockade and prolonged

the duration of analgesia compared with the fentanyl group.

3. Intrathecal fentanyl in a dose of 50 μg and Nalbuphine in a dose of 1.6 mg are

safe adjunct to Bupivacaine and have no added side effects to those of other

opioids.

4. Intrathecal fentanyl in a dose of 50 μg and Nalbuphine in a dose of 1.6mg have

no serious effect on heamodynamics as bradycardia and not cause serious

complication as respiratory depression.

5. Intrathecal fentanyl and Nalbuphine don't prolong the duration of spinal motor

block and hence don't interfere with postoperative mobilization.

Recommendations

71

RECOMMENDATIONS

From the current study, we recommend that:

1. Nalbuphine and fentanyl are good option to be added to intrathecal Bupivacaine

to improve the postoperative analgesia.

2. Further studies are recommended to be done for comparing the efficacy of

fentanyl and Nalbuphine when used intrathecally for postoperative analgesia and

long term chronic pain syndroms.

References

72

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الملخص العربي

1

الملخص العربي

بالنسبة للمرضى الذين يخضعون للجراحة. لا يجب أن إن تخفيف الألم بشكل فعال يعد من الاشياء الاكثر أهمية

يتحقق هذا لأسباب إنسانية فقط لكن يوجد الآن دليل على أن تخفيف الألم له تأثيرات فسيولوجية هامة. ليس فقط لان

لألم الفعال يؤدى لمرور مريح لفترة ما بعد العملية الجراحية مع الخروج في وقت مبكر من المستشفى ، لكنه قد تخفيف ا

يقلل أيضا من ظهور متلازمات الألم المزمن.

بساطة تقنية التخدير النخاعي والقدرة على الأعتماد عليها جعلتها واحدة من التقنيات المفضلة في جراحة

يمكن أن يسبب الألم أثناء العملية. زيادة زوال التأثير غير المتوقع للبنج النصفي أو طول مدة العملية الأطراف السفلية.

جرعة التخدير الموضعي و إضافة المواد الأفيونية إلى التخدير الموضعي في التخدير الشوكي من شأنه أن يكون مفيدا

يلة بعد الجراحة.لإطالة فترة إيقاف الألم والحفاظ على التسكين لفترة طو

كان الهدف من هذا العمل هو مقارنة تأثير النالوفين مقابل الفنتانيل كأضافات للبيبيفاكايين في التخدير النخاعي

فيما يتعلق بتسكين ما بعد الجراحة ، استقرار الدورة الدموية ، بداية الغلق العصبي الحسي ,الارتخاء العضلي ومدة

التثبيت الداخلي للساق. ون لجراحةالعمل في المرضى الذين يخضع

مريضا و الذى حدّد لهم سلفاً التثبيت الداخلي لعظمة الساق تحت تأثير التخدير 50أجريت الدراسة الحالية على

النصفى ، و قد تم تصنيفهم إلى مجموعتين:

% عن طريق 0.5بتركيز فاكينمل عقار الببيو 2ميكروجم + 50عقارالفنتانيل تم إعطائهم :المجموعة الاولي

التخدير النصفى.

% عن طريق 0.5بتركيز فاكينمل عقار الببيو 2مجم + 1.6عقارالنالبوفينتم إعطائهم المجموعة الثانية :

التخدير النصفى.

تم إجراء تقييم ما قبل الجراحة من خلال أخذ التاريخ المرضي الكامل والفحص البدني والتحاليل اللازمة.

المراقبة الأساسية بما في ذلك تخطيط القلب بتخدير العمود الفقري تم توصيل المرضي باجهزة قبل البدء

(ECG.وضغط الدم وقياس النبض. تم قياس قراءات المريض المبدئية قبل بدء التخدير النخاعي ، )

وضع الجلوس دقيقة ، ثم تم وضعهم في 15مل / كغ ، علي مدار 10تلقى المرضى قبل العملية محلول رينغر

، بعد الحقن ، استلقي المرضي مع وضع 25القطنية باستخدام إبرة قياس 4و3وتم إجراء التخدير النخاعي بين الفقرات

لتر / دقيقة طوال العملية. 5الرأس على وسادة. أعطي الأكسجين بمعدل

الملخص العربي

2

القياسات

)بالكيلوجرام( والطول )بالسنتيميتر(البيانات الديموغرافية: العمر )بالسنة( والجنس والوزن (1

، تم تسجيل قراءة معايير الدورة الدموية: معدل ضربات القلب )دقات / دقيقة( ، متوسط ضغط الدم الشرياني (2

دقيقة حتى نهاية الإجراء. 15، دقائق ، وبعد ذلك كل 10، 8، 6، 4، 2دقائق قبل الحقن ثم في 5مبدءية

15الانحدار لشريحتين و الذى يتم تقييمه كل وقت )بالدقائق( لبداية الشلل الحسي ، وقتتقييم الإحساس: ال (3

دقيقة عن طريق اختبار الثلج البارد.

تقييم الوظيفة الحركية: وقت بداية الشلل الحركي)بالدقائق( : من نهاية الحقن حتى يصل المريض إلى الشلل (4

قييم بروماج( الحركي الكامل )وصوله للدرجة الثالثة بت

( إلى الوقت الذي 3مدة الشلل الحركى: من وقت وصول المريض للشلل الحركى الكامل )معدل بروماج

دقيقة 30استطاع فيه المريض رفع ساقيه في الفراش ضد الجاذبية )معدل بروماج صفر( كل

بات القلب ، هبوط معدل بما في ذلك )انخفاض ضغط الدم ، بطء ضر الآثار الجانبية: حدوث آثار جانبية (5

التنفس ، الحكة ، الرجفة ، الغثيان والقيء(.

( في فترة ما بعد VASتسكين بعد العملية الجراحية: مدة التسكين باستخدام مقياس التماثلية البصرية ) (6

ساعة الأولى ، قياس وقت 24ساعات لبقية ال 6ساعات ، ثم كل 8الجراحة مباشرة ، ثم كل ساعتين لأول

طلب أول مسكن.

تم احتساب الجرعة الإجمالية لديكلوفيناك الصوديوم العضلي. (7

أظهرت نتائج الدراسة الحالية ما يلي:

فيما يتعلق بالسن والوزن والطول ومدة الجراحة. لم يكن هناك فرق ذو دلالة إحصائية بين المجموعتين •

ملحوظ بعد التسكين الشوكي ، ولكن لم يكن هناك فرق في المجموعتين انخفض ضغط الدم الشرياني بشكل •

الدراسة. أحصائي بين المجموعتين فيما يتعلق بمعدل ضربات القلب والضغط الشرياني على مدار وقت

لم يكن هناك فرق أحصائي بين المجموعتين فيما يتعلق ببداية ، ومدة الشلل الحسي ومدة الشلل الحركى على •

مدار وقت الدراسة.

في مجموعة المرضى الذى تلقوا الفينتانيل عن المجموعة التى تلقت النالوفن بدأ الشلل الحركى أسرع •

مدة التسكين كانت أطول بكثير في مجموعة المرضى الذى تلقوا النالوفن عن المجموعة التى تلقت الفينتانيل •

ية من الصوديوم ديكلوفيناك بين لم يكن هناك اختلاف كبير في وقت طلب أول مسكن والجرعة الإجمال •

المجموعتين.

.في المجموعتين لم تحدث أي حالات هبوط لمعدل التنفس أو بطء فى معدل ضربات القلب •

الملخص العربي

3

فيما يتعلق بانخفاض الضغط و الارتعاش والحكة والغثيان والقيء لم يكن هناك فرق بين المجموعتين •

المدروستين على مدار وقت الدراسة.

الدراسة ، يمكن استنتاج ما يلي:من هذه

تسكين العمود الفقري يلعب دورا هاما في توفير تسكين مرضي لفترة ما بعد العملية الجراحية خالي من . 1

العقاققير الافيونية.

٪( قد أدى إلى إطالة زمن 0.5ملغ إلى بوبيفاكايين في التخديرالشوكي )بتركيز 1.6إن إضافة النالبوفين . 2

الحصار الحركي وطول مدة التسكين مقارنة مع مجموعة الفنتانيل.بداية

ملغ اضافة آمنةً لبوبيفاكايين وليس لهما 1.6ميكروغرام ونالبوفين بجرعة 50تعتبر مادة الفنتانيل بجرعة . 3

أي آثار جانبية مضافة لتلك الخاصة بالمواد الأفيونية الأخرى.

ملغ ليس لهما أي تأثير خطير على الديناميكا 1.6والنالبوفين بجرعة ميكروغرام 50الفنتانيل بجرعة . 4

الدموية مثل بطء نباضات القلب ولا يسببوا مضاعفات خطيرة كهبوط معدل التنفس.

وبالتالي لا يتداخلان ببدءالحركة بعد العملية مدة الشلل الحركىالتخدير الشوكي بالفنتانيل والنالبوفين لا يطيل . 5

.الجراحية

التوصيات

النالبوفين والفنتانيل خياران جيدان لإضافتهما إلى بوبيفاكايين في التخدير الشوكي لتحسين تسكين الألم بعد . 1

العملية الجراحية.

يوصى بإجراء مزيد من الدراسات لمقارنة فعالية الفنتانيل ونالبوفين عند استخدامها في التخدير الشوكى . 2

ومتلازمات الألم المزمن. لتسكين ما بعد الجراحة