Ambulance Analgesia

This paper will compare and contrast the use of morphine and fentanyl as pre-hospital analgesia.

Pharmacokinetics and pharmacodynamics of fentanyl.

Administration and absorption

Fentanyl can be administered intravenously (IV), subcutaneously (SC),intranasally (IN), as a transdermal patch (TD) and as an oral transmucosal lollipop (OTM) (MIMS 2003, p 4-359; Bryant and Knights 2003, p. 247). IV administration has the most rapid onset of action, followed by OTM, IN, SC and TD being the slowest. Unlike most other opioids, which have to be primarily administered parentally, fentanyl can be administered via both the parental and enteral routes, without any major reduction in bioavailability as a result of a first pass metabolism within the liver (Galbraith, Bullock, and Manias 2001, p. 366).

IV and SC administration may be useful when analgesic requirements makes oral dosing impractical as well as patients who require rapid titration of opioids for pain relief. Medications may be given as repeated intermittent bolus doses or by continuous infusion (Bryant and Knights 2003, p. 247). IV administration provides ‘almost immediate analgesia where as SC may require up to 15 minutes for full effect’ (MIMS Annual 2003, p. 4-365). Bolus IV dosing provides a shorter duration of action than other routes, while continuous infusions provide steady blood levels (Weiner 2002, p. 482). Because of its high affiliation with lipids fentanyl is readily absorbed via the skin.  Bryant and Knights states that: ‘fentanyl is highly lipophilic making it easily administered TD’ (2003, p. 247). Plasma levels rise slowly over 12-18 hours after transdermal patch placement and slowly fall off 20-24 hours after removal (Oh 1998, p.681), making it very easy to use, and ‘practical for chronic pain disorders, especially cancer’ (Galbraith, et Al 2001, p. 366). 

When fentanyl is administered in the oral transmucosa, in the form of a lollypop, it acts in a ‘combination of an initial rapid absorption from the buccal mucosa (parenteral absorption) and a more prolonged absorption of swallowed fentanyl from the gastro-intestinal tract (enteral absorption)’ (Loeser 2001, p. 98). Both the blood fentanyl profile and the bioavailability of fentanyl will vary depending on the fraction of the dose that is absorbed through the oral mucosa and the fraction swallowed. Fentanyl is metabolized primarily in the liver and intestinal tracts which would suggest that any enteral administration of the drug would be ineffectual due to a first-pass mechanism. However, according to Evan, Kharasch, Whittington and Hoffer the ‘first-pass metabolism has little effect on fentanyl’s bioavailability from oral transmucosal fentanyl’ (2003, p1). Furthermore the buccal absorption, bioavailability, and permeability of fentanyl are markedly increased as the pH of the fentanyl solution becomes more basic. This is because of ‘an increase in the fraction of unionized fentanyl’ (Streisand, Zhang, Suyi, McJames, Remco, Pace 1995, p. 759). Intranasal fentanyl is an alternative route when the oral route is unavailable.

The IN route provides for rapid absorption and onset of action. According to Striebel, Kramer, Luhmann, Rohierse-Hohler and Rieger: ‘intranasal fentanyl seems to be a promising, non-invasive and rapid-acting new mode of opioid administration that is especially suitable in acute pain syndromes’ (1993, p.1). Acording to Hill ‘intramuscular injections should be avoided because injectionsare painful, inconvenient and absorption is erratic, meaning that the benefits do not out way the negatives’ (Hill 97, p. 3).

Distribution

According to the MIMS Annual the ‘distribution time of fentanyl is 1.7 minutes, redistribution is 13 minutes and the terminal elimination half-life is 219 minutes’ (MIMS Annual 2003, p. 4-359). According to Weiner ‘fentanyl is highly lipid soluble, causing it to have a rapid onset of action with a large volume of distribution and a relatively short duration of action’ (2002, p. 482). The mean volume of distribution at a steady state is 4 L/kg (MIMS Annual 2004, p.4-359). The analgesic effects of fentanyl may appear before the adverse effects, when administered IV. According to MIMS annual: ‘the onset of action may be immediate when administered IV; however the maximal analgesic and respiratory depressant effect may not be noted for several minutes’ (MIMS Annual 2003, p. 4 –359). 

A proportion of all drug molecules entering into the blood stream bind to proteins to form drug-protein complexes. ‘Acidic drugs bind mainly to albumin, while basic drugs bind to acid glyco-proteins contained in the blood’ (Bryant and Knight 2003, p.108). Because of the size of the molecules formed by plasma protein drug complexes, drugs which are bound to proteins cannot pass through the plasma membrane of the vascular system, and are therefore unable to cause their desired effects on their target cells or organs. Galbraith et al states: ‘the stronger the protein binding, the less of the free drug that will be present in the plasma and the longer the drug will remain within the vascular system increasing the drugs ½ life’ (1998, p.1081). Therefore, one would determine that because fentanyl is highly plasma protein bound at 85% it would remain within the vascular system longer than morphine, which is only 35% protein bound (MIMS Annual 2003, p. 4-359). However, due to its highly lipophilic nature and the fact that it has a pKa (ionization) of 8.2 its rate of distribution and onset of action is more rapid than morphine, causing its half-life to be considerably shorter (Streisand et al 1995, p. 759).

Metabolism

Fentanyl is highly metabolized by the liver, decreasing the effect of any orallyadministered but not leaving it ineffectual. Fentanyl is primarily (more than 90%) eliminated by biotransformation to inactive metabolites (MIMS Annual 2003, p. 4-359).

Excretion

The metabolites are mainly excreted in the urine while fecal excretion is lessimportant. The total plasma clearance of fentanyl is 0.5 L/hr/kg (MIMS Annual 2003, p. 4-359). The terminal elimination half-life after OTM administration is about 7 hours. Approximately 75% of an IV dose is excreted via the kidneys in urine as metabolites with less than 10% representing the unchanged medicine. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites (MIMS Annual 2003, p. 4-359; Bryant and Knights 2003, p. 244-5).

Pharmacodynamics

Similar to other opiates, fentanyl acts as an agonist to bind with specific receptor sites in the brain, spinal cord and many other tissues, called opioid receptors. The body’s endogenous opiate receptor sites are known as ‘delta, epsilon, kappa and mu’ (Galbraith et al 2001, p.336). These are inhibitory neurotransmitters, which suppress pain messages to the CNS from the periphery. Fentanyl exerts its primary effect on the central nervous system (CNS) and organs containing smooth muscle. Effects include: ‘miosis, respiratory stimulation followed by depression, bradycardia, hypothermia, and a decrease in nociception’ (Loeser 2001, p. 99). There are high concentrations of receptors for the body’s natural opioids such as the endorphins and enkephalins in many areas of the CNS, particularly in the ‘grey matter of the midbrain, the limbic system and at the interneurons in the dorsal horn areas’ (Bryant and Knights 2003, p. 235). These areas are known to be involved in pain transmission or perception.

Fentanyl acts by binding to the mu and kappa receptor sites and in doing so blocking the transmission of the theoretical substance P (pain) through a variety of inhibition processes. According to Loeser the opioid receptor is ‘a gene-protein- coupled (G-protein) receptor that can work via a number of effectors and second messengers to influence a variety of neuronal processes’ (Loeser 2001, p.101). This leads to an inhibition both presynaptic and postsynaptic of transmitter release, and hence a decrease in nociception. Through G-protein coupling, opiate receptors can ‘activate potassium (K)channels, close calcium (Ca) channels or both’ (Loeser 2001, p. 102). In doingso, they cause a decrease in intracellular cyclic Adenosine Monophosphate (cAMP)levels and therefore result in a ‘reduction of chemical transmitter release and hencea blockade of synaptic transmission’ (Munson 1998, p. 408). Opiate receptors can also act on the O and I alpha G-protein subunits to inhibitadenylate cyclase and thus reduce the production of cAMP from adenosinetriphosphate (ATP). This, in turn, causes an inhibition of cAMP-dependant proteinkinase (PKC) and the transmission of substance P (Appleyard 1998, p. 14; Galbraith et al 1997, p.335). Decreased cAMP levels lead to a decrease in ‘neuronal excitability leading to inhibitory effects at cellular level; effects that appear to be excitory are actually due to the suppression of firing of in inhibitory neurons’ (Bryant and Knights 2003, p. 245).

At the spinal level fentanyl stimulates the ‘opioid mu receptors in the dorsal horn of the spinal cord’ (Galbraith et al 2001, p.362) and thus inhibits the release of substance P from the dorsal horn neurons. At supraspinal levels ‘opiates act to close the gate in the dorsal horn, thus inhibiting afferent transmission of the substance P’ (Bryant and Knights 2003, p 245). It is also capable of altering perception and emotional responses to pain because opiate receptors are widely distributed in the CNS, especially in the limbic system, thalamus, hypothalamus and midbrain (MIMS Annual 2003 p. 4 –433). When pain perception is inhibited the analgesic effect of an opioid is enhanced.

Fentanyl rarely causes a clinically significant histamine response such as morphine. Because of this, adverse effects such as hypotension are not as likely, making it a more suitable drug for patients who are haemodynamically unstable. OH states that ‘fentanyl has fewer adverse effects on the cardiovascular system, and can be used in patients with haemodynamic instability in whom morphine may cause severe hypotension’ (Oh 1998, p. 680).

Contrasting the pharmacology of fentanyl and morphine

 Fentanyl absorption Fentanyl can be administered IV, SC, IN, TD and as an OTM (MIMS 2004, p. 4- 359; Bryant and Knights 2003, p. 247). Unlike most other opioids, which have to be administered parentally, fentanyl can be administered via both the parental and enteral routes, without any major reduction in bioavailability due to the first pass metabolism within the liver (Galbraith et al 2001, p. 366). Morphine absorption Morphine can be administered via ‘SC, IM, IV injection and as an oral tablet; however due to the fact that it is highly metabolism by the liver, its first pass mechanism reduces its bioavailability to all but 40% of the ingested dose (MIMS Annual 2003 p. 4-433).

Fentanyl distribution According to the MIMS Annual the ‘distribution time of fentanyl is 1.7 minutes, redistribution is 13 minutes and the terminal elimination half-life is 219 minutes’ (MIMS Annual 2003, p. 4-359). According to Shoemaker, Ayres, Grenwick and Holbrook, ‘fentanyl is approximately 500 fold more lipophilic than morphine’ (2000, p.300), which is the cause for its rapid onset of action. The plasma protein binding of fentanyl is 80-85% and the free fraction of fentanyl increases with acidosis. The mean volume of distribution at a steady state is 4 L/kg (MIMS Annual 2003, p. 4-359). The analgesic effects of fentanyl may appear before the adverse effects, when administered IV. Fentanyl reaches its peak effect in 2-3 minutes, which not only brings very rapid pain relief, but also allows safer titration. Morphine distribution Morphine is not particularly highly protein bound at ‘35% being bound to plasma protein’ (Bryant and Knights 2003, p247) and is relatively hydrophilic when compared to fentanyl, so it crosses slowly into the CNS. Because of this, its distribution time is relatively long. Approximately 20 minutes post IV administration (MIMS Annual 2003 p. 4 –364). Plasma half-life is achieved between 2-3 hours after administration (MIMS Annual 2003 p. 4 –433). IV morphine does not reach its peak effect until about 15 minutes, meaning that pain relief is relatively slow, by comparison to fentanyl, and the chance of opioid overdose through poor titration is more likely.

Fentanyl metabolism Fentanyl is highly metabolized by the liver, decreasing the effect of any orallyadministered fentanyl but not leaving it ineffectual (MIMS Annual 2004, p. 4-359). Morphine metabolism Morphine is metabolized by the liver to form ‘morphine-3-glucuronide (M3G) and morphine –6-glucuronide (M6G), which are both inactive metabolites’ (Bryant and Knights 2003, p. 249). 

Fentanyl excretion The metabolites are mainly excreted in the urine while fecal excretion is less important being less than 0.01%. The total plasma clearance of fentanyl was 0.5 L/hr/kg. The terminal elimination half-life after OTM administration is about 7 hours. Approximately 75% of an IV dose is excreted in via the kidneys in urine as metabolites with less than 10% representing the unchanged medicine. Approximately 9% of the dose is recovered in the faeces, primarily as metabolites (MIMS 2003, p. 4-359). Morphine Excretion Morphine is primarily excreted via the kidneys, and small amounts are excreted as bile and faeces (MIMS Annual 2003 p. 4 –433). Because both fentanyl and morphine are principally excreted via the kidneys any decrease in the glomerulus filtration rate (GFR) due to young age, old age or nephological disease may result in ‘maintained  higher serum levels and a longer duration of action than intended’ (Sanders 2001, p.261).

Fentanyl and Morphine pharmacodynamics

Fundamentally, because both fentanyl and morphine act on opioid receptors as their primary mechanisms of action, many of the pharmacodynamics between the two drugs are similar. Both fentanyl and morphine act as an agonist to bind with specific receptor sites in the brain, spinal cord and many other tissues, called opioid receptors. The body’s endogenous opiate receptor sites are known as ‘delta, epsilon, kappa and mu’ (Galbraith et al 2001, p.336). These are inhibitory neurotransmitters, which suppress pain messages to the CNS from the periphery. However, where fentanyl and morphine differentiate is by the specific opioid receptors that they bind with, and how much of a reaction they cause. Specifically, fentanyl stimulates the mu receptor sites +++ and the delta receptor +, with no effect on the kappa or epsilon receptors. Morphine, however, stimulates both the mu and delta sites similarly to fentanyl, but also acts on the kappa receptors sites + which may be the cause of some divergent pharmacodynamics as a result of choosing between the two forms of analgesia (Rang, Dale, and Ritter 1999, p.593).

Fentanyl and morphine exert their primary effect on the CNS and organs containing smooth muscle. Effects include: ‘analgesia, drowsiness, alteration in mood (euphoria), reduction in body temperature, depression of the respiratory drive, cough suppression and miosis’ (Hollinger 1997, p. 384). There are high concentrations of receptors for the body’s natural opioids such as the endorphins and enkephalins in many areas of the CNS, particularly in the ‘grey matter of the midbrain, the limbic system and at the interneurons in the dorsal horn areas’ (Bryant and Knights 2003, p. 235). These areas are known to be involved in pain transmission or perception. Although the delta, epsilon, kappa and mu receptor sites have all been associated with producing nociception, the mu receptor site is the most prominent in the reduction of pain. It is primarily the mu receptor sites that both fentanyl and morphine act upon to produce analgesic effects. By binding opioids to the mu receptor sites the transmission of the substance P through a variety of inhibition processes occurs.

According to Loeser the opioid receptor is ‘a gene-protein- coupled (G-protein) receptor that can work via a number of effectors and second messengers to influence a variety of neuronal processes’ (Loeser 2001, p.101). This leads to an inhibition both presynaptic and postsynaptic of transmitter release, and hence a decrease in nociception. Through G-protein coupling, opiate receptors can ‘activate potassium (K)channels, close calcium (Ca) channels or both’ (Loeser 2001, p. 102). In doingso, they cause a decrease in intracellular cyclase Adenosine Monophosphate(cAMP) levels and therefore result in a ‘reduction of transmitter release and hencea blockade of synaptic transmission’ (Munson 1998, p. 408). Opiate receptors can also act on the O and I alpha G-protein subunits to inhibit adenylate cyclase and thus reduce the production of cAMP from AdenosineTriphosphate (ATP). This, in turn, causes an inhibition of cAMP-dependant proteinkinase (PKC) and the transmission of substance P (Appleyard 1998, p. 14;Galbraith et al1997, p.335). Decreased cAMP levels lead to a decrease in ‘neuronal excitability leading to inhibitory effects at cellular level; effects that appear to beexcitory are actually due to the suppression of firing of in inhibitory neurons’ (Bryant and Knights 2003, p. 245). 

Although both fentanyl and morphine act on the mu receptor sites fentanyl rarely causes the clinically significant histamine response seen in the administration of morphine. Because of this, adverse effects of hypotension are not as likely and may be more suitable for patients who are haemodynamically unstable. Oh states, that ‘fentanyl has fewer adverse effects on the cardiovascular system, and can be used in patients with haemodynamic instability in whom morphine may cause severe hypotension’ (Oh 1998, p. 680).

Because both fentanyl and morphine act on the mu receptor sites they cause a decrease in gastric intestinal motility and an increase in the desire to vomit (Rang, Dale, and Ritter 1999, p.593); however, according to the MIMS Annual ‘fentanyl appears to have less emetic activity than morphine’ (2003, p. 4-359) which may be very beneficial in patients in the prehospital care setting who may already have unstable airways, and have not fasted. Fentanyl may be the drug of choice to avoid the risk of the likely emetic results stimulated by such analgesia as morphine. The exact probability that a molecule will be protonated or deprotonated depends on the pKa (ionization) of the molecule and the pH of the solution. Fentanyl has a pKa of 8.2 where as morphine has a pKa of 7.9 (Sansom 2004, p.284). Therefore, by having a higher pKa (and a greater affiliation with lipids) fentanyl crosses over the plasma membrane more rapidly than morphine. Investigating the risks and benefits of fentanyl for analgesia in thepre-hospital care setting  Risks Like all opioids the major adverse effects of fentanyl are respiratory depression and sedation.

Fentanyl causes ‘a diminished sensitivity to CO2 resulting in a depressed respiratory drive’ (MIMS 2003, p. 4-359). Because of this, the use of fentanyl as analgesia in patients with limited respiratory reserve, such as those with chronic airway limitations (CAL) or chronic obstructive pulmonary disease (COPD) should be tentative and with close monitory of the patient’s conscious state, effectiveness of respirations (rate and depth), O2 saturations, skin colour and HR to ensure adequate perfusion is maintained.

 According to the therapeutic goods administration, due to its ‘cholinergic stimulation’ fentanyl may ‘produce bradycardia and possibly asystole’ (TGA 2003, p.2). This resultant bradycardia may be treated with atropine; however, ‘fentanyl should be used with caution in patients with cardiac bradyarrhythmias’ (MIMS Annual 2003, p. 4-359). This is a result of possible cholinergic stimulation, which is why atropine may be used in its treatment. According to the TGA ‘the inclusion of atropine or other anti-cholinergic agents in the pre-anaesthetic regimen tends to reduce the occurrence of bradycardia and other unwanted cholinergic effects (TGA 2003, p.1). According to the TGA ‘severe and unpredictable potentiation by MAO inhibitorshas been reported with opioid analgesics and the use of fentanyl in patientswho have received MAO inhibitors within 14 days is not recommended’ (TGA 2003,p.2). One of the more common adverse effects when administered with MAO inhibitors is a hypertensive crisis leading to cerebral vascular accidents (CVAs) and death (Jarvis 2005, p. 2).

Fentanyl is an synthetic opiate derivative, and therefore may cause physiologicaland psychological dependence commonly associated with the use of opioids (Galbraith et al 2003, p. 350-2; Oh 1998, p.679-83). However, judicious use of fentanyl in the treatment of actual pain should not be withheld due to an inherent risk of physiological and possible psychological dependence. ‘Patients on chronic opioid therapy or with a history of opioid abuse may requirehigher doses to achieve an adequate therapeutic effect’ (TGA 2003, p.2). Because 75% of fentanyl administered IV is metabolized by the liver and primarily excreted by the kidneys, its dose must be decreased to compensate in patients with hepatic disease or renal failure who fail to metabolize and excrete fentanyl as rapidly as healthy patients (MIMS 1998, p. 4 –359). Myasthenia gravis (MG) is one of a group of neuromuscular diseases. Neuromuscular diseases effect how your nerve pathways communicate with your muscles. With MG, the muscle does not always get messages to move parts of your body. According to MIMS Annual fentanyl ‘may cause muscle rigidity in patients with myasthenia gravis’ (MIMS 1998, p. 4-359). Alcohol and other CNS depressants potentiate effects, making it possible for overdoses, leading to respiratory failure and death.

Benefits

Fentanyl rarely causes a significant histamine response, as seen in the administration of morphine (Marik 2002, p. 706), therefore does not have such adverse effects as hypotension and may be more suitable for patients who are haemodynamically unstable. According to Oh, fentanyl ‘has fewer adverse effects on the cardiovascular system, and can be used in patients with haemodynamic instability in whom morphine may cause severe hypotension’ (Oh 1998, p. 680). Fentanyl is unlikely to provoke nausea and vomiting. According to the MIMSAnnual ‘fentanyl appears to have less emetic activity than morphine’ (MIMS 1998, p.4-359). This is specifically beneficial in patients with trauma, head injuriesand an unstable airway. By avoiding drugs with the high likelihood of emetic results, one avoids vomitus blocking the airway, the possible raised intracranialpressure (ICP) caused by vomiting, and the unnecessary use of anti-emetic agents such as metoclopramide and their potential adverse effects (Marik 2002, p. 702-7).

According to Weiner ‘due to fentanyl’s lipid solubility, it has a rapid onset,large volume of distribution and a relatively short duration of action’ (Weiner2002 , p.482). This may be very beneficial because it allows for rapid onsetof analgesia and safer titration. Because it is an opioid it may be antagonized rapidly with the use of naloxone,which acts by ‘competitively blocking opioid receptor sites’ (Oh 1998, p. 681). Therefore, any overdoses may be rapidly corrected. Special Forces medics administration OTM fentanyl during operation Iraqi Freedom to 22 patients with trauma and in that time found that ‘oral transmucosal fentanyl is an effective analgesic with a rapid onset, and limited adverse effects’ (Kotwal, O’Connor, Johnson, Mosely, Meyer, Holcomb 2004, p.1).

What analgesia would work best for paramedics in providing prehospital care?

According to Lord: ‘it’s crucial for members of the health care team to acknowledge and support the expansion of the paramedic’s role as a frontline pain manager’(Lord 2004, p.52). In order to do this successfully more rapid and effective methods of analgesia must be available for pre-hospital care (PHC) workers. Drugs such as IV, IN and OTM fentanyl should be made available to PHC workers and their educational and training levels brought up to a level that they know exactly how to use it effectively without fear limiting their use of it. To this day, apprehensions about adverse effects arising from analgesic use and the influence that administration of analgesics may have on the diagnostic process have been indirectly implicated. According to the National Health and Medical Research Council, evidence that the ‘relief of pain may actually enhance the diagnostic process refutes the contention that opioids mask symptoms andcomplicate the diagnosis’ (NHMRC, 1999). Therefore the only way to decrease such fallacies is to promote education and training so that PHC workers feelcomfortable in administering the type of drugs and enough of them required toactually treat the pain.

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