Local anaesthetics: Theoretical aspects

Physiology of pain

The sensation of acute pain arises from the activation of peripheral nociceptors secondary to local inflammation or trauma. Through the activation of sodium channels, this causes depolarisation of either fast conducting, myelinated A-delta nerves (sharp pain) or slower conducting, unmyelinated C fibres (dull, visceral pain) which travels to the central nervous system whereby an unpleasant sensation is experienced (Yam et al., 2018).

Local anaesthetic mechanism of action

Local anaesthetics exert their mechanism of action by blocking sodium channels, thereby preventing the depolarisation of peripheral nerves. By preventing an influx of sodium, the resting membrane potential of the nerve axon is altered, and the propagation of an action potential is therefore inhibited.

Local anaesthetics are highly lipid soluble molecules, meaning that they readily pass through the phospholipid bilayer surrounding the nerve axon. Once inside the nerve cell, the local anaesthetic molecule becomes ionised, and therefore, is unable to pass back through the cell membrane and stays trapped within the nerve. Here, they bind to the inside of active sodium channels, preventing the return to their resting state, and hence, inhibiting the transmission of further neuronal impulses (Peck et al., 2008).

Physicochemical properties

Structurally, local anaesthetics are either esters or amides. These two molecules share two common parts. A hydrophilic, tertiary amine tail is connected by either an ester or amide link to a lipophilic aromatic ring (Becker and Reed, 2006).

A useful aide memoir to recall the members of each category is that the ester local anaesthetics do not contain the letter ‘i’ before the suffix ‘_caine’ (e.g. procaine, amethocaine and cocaine) whereas the amides do (e.g. lidocaine, prilocaine, bupivacaine and ropivacaine). The structural differences between these two categories are reflected in their different properties, particularly with regards to pharmacokinetic behaviour.

The most notable differences between the two categories of local anaesthetic are in their metabolism and elimination. For the most part, esters are rapidly hydrolysed in the blood by plasma cholinesterases; this leads to the production of the metabolite para-aminobenzoate (PABA), which is often the responsible compound in patients allergic to local anaesthetics. Amides, on the other hand, are metabolised hepatically, and so are less likely to cause an allergic reaction (Peck et al., 2008).

The ratio of un-ionised to ionised local anaesthetic molecules accounts for the varying speed of onset and potency seen between different local anaesthetic preparations. Given that the ratio of ionisation of a molecule is dependent on the pH of the surrounding environment, in the acidic environment of infected tissue, there are fewer un-ionised local anaesthetic molecules available to cross into the nerve cell, and therefore, action potentials may still be generated. It is for this reason that local anaesthetics are often less effective if used in an attempt to anaesthetise infected tissue, e.g. an abscess (Peck et al., 2008).

As with many other medications, the lipid solubility of a local anaesthetic preparation is partially responsible for its potency. Highly lipid soluble local anaesthetics freely diffuse through the neuronal cell membrane, and so relatively smaller doses are needed to achieve a comparable pharmacological effect (Peck et al., 2008).

The degree of protein binding of the local anaesthetic is proportional to its duration of action. Highly protein bound local anaesthetics (e.g. bupivacaine) have a substantially longer duration of action than those with lower protein binding (e.g. lidocaine) at equipotent doses. A mixture of two different local anaesthetic preparations can be administered in order to take advantage of desirable properties of each. This can achieve a fast onset, but long-lasting anaesthesia if required for a specific procedure. Table 1 shows the physicochemical differences in some commonly used local anaesthetics (Peck et al., 2008).

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Table 1.

Pharmacological properties of commonly used local anaesthetics.

	pKa	Speed of onset	Relative lipid solubility	Potency	Protein binding (%)	Duration of action
Prilocaine	7.7	Fast	50	Low	55	Moderate
Lidocaine	7.9	Fast	150	Moderate	70	Moderate
Bupivacaine	8.1	Moderate	1000	High	95	Long
Amethocaine	8.5	Slow	200	High	75	Long

Solution for injection

Local anaesthetics come in many different preparations, however, they are most often found in a solution for subcutaneous injection. This preparation is extremely versatile and is most often used when performing minor surgery in general practice. The local anaesthetic will often come as a ‘plain’ solution, often containing a preservative. This may be mixed with other medications or substances in order to alter their pharmacokinetic and pharmacodynamic properties. Most commonly in primary care, local anaesthetics are mixed with adrenaline. This combination causes small vessel local vasoconstriction, thereby counteracting the vasodilatory effects of the local anaesthetic. This causes a prolonged effect of the local anaesthetic, due to a reduction in systemic uptake, as well as acting to reduce local bleeding. The prolonged effect of local anaesthetics containing adrenaline can allow for smaller volumes to be used, and so reduce the distortion of normal anatomy during minor surgery. In addition to this effect, the addition of adrenaline to a mixture of lidocaine will increase the safety profile of the medication (again due to the reduced systemic uptake of local anaesthetic), allowing for a higher dose to be safely used. The maximum doses of some local anaesthetics are shown in Table 2 (Peck et al., 2008).

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Table 2.

Doses of commonly used local anaesthetics.

	Maximum dose (ideal body weight, see equations below)
Local anaesthetic preparation	Dose per kg	50 kg	60 kg	70 kg	80 kg	90 kg
Lidocaine 1%	3 mg/kg	150 mg (15 ml)	180 mg (18 ml)	210 mg (21 ml)	240 mg (24 ml)	270 mg (27 ml)
Lidocaine 1% with adrenaline	7 mg/kg	350 mg (35 ml)	420 mg (42 ml)	490 mg (49 ml)	560 mg (56 ml)	630 mg (63 ml)
Bupivacaine 0.25% with or without adrenaline	2 mg/kg	100 mg (40 ml)	120 mg (48 ml)	140 mg (56 ml)	160 mg (64 ml)	180 mg (72 ml)
Bupivacaine 0.5% with or without adrenaline	2 mg/kg	100 mg (20 ml)	120 mg (24 ml)	140 mg (28 ml)	160 mg (32 ml)	180 mg (36 ml)

If using adrenaline-containing preparations, it is important to acknowledge the potential drawbacks of this approach. Traditional teaching has suggested that the use of an adrenaline-containing local anaesthetic mixture is contraindicated in any area of the body in which blood supply may be compromised if local vasoconstriction occurs, for example, the digits, ears, nose or penis. However, it has been suggested that the use of an adrenaline-containing local anaesthetic preparation in finger and hand surgery is safe and is not associated with the previously feared theoretical risks (Chowdhry et al., 2010).

Inadvertent intravascular injection of local anaesthetic is possible when attempting to anaesthetise subcutaneous tissue, however, the adoption of correct surgical technique should reduce the likelihood of this event occurring. If an adrenaline-containing local anaesthetic mixture is injected intravascularly in this circumstance, the recipient may become flushed and hypertensive or complain of palpitations. This should alert the clinician to stop injecting the solution and reposition the needle tip before continuing infiltration.

It is also important to understand the potentially confusing nomenclature when it comes to choosing the correct concentration of both local anaesthetics and adrenaline. Local anaesthetics are commonly referred to with regards to a percentage concentration. Using the example of lidocaine, 1 ml of 1% lidocaine contains 10 mg of local anaesthetic whereas 1ml of 2% lidocaine contains 20 mg of local anaesthetic. Importantly, adrenaline concentration is named differently, whereby 1 mL of 1:1000 adrenaline contains 1 mg of adrenaline. The amount of adrenaline added to a local anaesthetic mixture will vary depending on intended use and clinician preference; however, a commonly used preparation in primary care includes adrenaline at a concentration 1:200 000.

The initial subcutaneous injection of local anaesthetics is painful, and is often the most unpleasant part of minor procedures (Zilinsky et al., 2005). It is possible to anaesthetise an area inflicting minimal pain; however, this requires the user to establish an effective technique. Prior preparation of the local anaesthetic by warming the solution to body temperature or by the addition of bicarbonate (in order to better match the pH of the solution to the pH of the skin) can reduce pain on injection, however, the amount of bicarbonate needed in order to ‘neutralise’ the local anaesthetic in the volumes that are often used in primary care is extremely small, and may potentially lead to complications of inaccurate drug dilution, and so is perhaps best avoided. A simpler approach to minimising pain on injection of local anaesthetic may be to use a smaller gauge needle (27G or 30G) and not repeatedly using the same needle, as this leads to a gradual blunting. Although the use of these smaller needles may be effective in minimising pain, with a reduction in gauge often comes a reduction in needle length, therefore increasing the number of dermal punctures required to anaesthetise a larger area. When choosing the most appropriate needle for local anaesthetic infiltration, it may be best to first consider the size and shape of the area to be anaesthetised, and selecting a needle that best compromises gauge with the number of fresh skin punctures that will be required.

Simple distraction techniques (both conversational and tactile) as well as ‘looking away’ have also been shown to reduce perceived pain on injection. Paying careful attention to the manipulation of one’s needle is also important in reducing injection-associated pain. By injecting into the subdermal layer (rather than intradermal), at a 90° angle to the skin and using an ‘inject, stop and go’ technique all help to reduce local anaesthetic-related pain. By ensuring the bleb of local anaesthetic is at least 10 mm in front of the needle tip at all times helps ensure that further advancements of the needle are only ever into already anaesthetised tissue (Strazar et al., 2013).

Topical

Local anaesthetics are also available in topical preparations. These preparations have the advantage of being very easy to apply and are often utilised in the anxious or non-compliant adult or child. There are a number of local anaesthetic creams available; however, a eutectic mixture of local anaesthetic (EMLA) and Ametop are two that are commonly used. EMLA cream is a mixture of lidocaine and prilocaine. Combining these two local anaesthetics allows the otherwise crystalline solid compounds to form an oil mixture, due to a reduction in boiling point (Peck et al., 2008). Application of the cream followed by a clear dressing 60 minutes prior will provide satisfactory analgesia for minor interventions lasting less than 2 hours, such as venesection or cannulation (Emla, 2019). The cream should not be applied to mucus membranes (due to increased systemic absorption) and should be used in caution in those with known methaemoglobinaemia or in those taking predisposing medications. Ametop is a topical preparation of tetracaine and may be used similarly to EMLA, however, has a quicker onset (30 minutes) and longer action (3 to 4 hours), however, it may cause some local skin irritation and erythema due to vasodilatation (Peck et al., 2008).

Other uses of local anaesthetics

As well as being used in minor surgery and in aiding venepuncture and cannulation, local anaesthetics may have a number of other uses in primary care. These include in the treatment of post-herpetic neuralgia, aphthous ulcers or haemorrhoids.

The National Institute for Health and Care Excellence (NICE) suggests that along with simple analgesia and neuropathic analgesics (e.g. amitriptyline), post-herpetic neuralgia may be treated using lidocaine plasters if the pain is mild, if there are concerns regarding central nervous system side effects of oral medications or as an adjunct to oral medications if pain is severe. Each plaster contains 5% lidocaine and should be worn for a maximum of 12 hours, followed by a 12-hour break in order to help prevent skin irritation. These plasters may be cut to fit the area of pain, or two to three plasters may be combined in order to achieve a wider area of anaesthesia. It is suggested that this treatment is reviewed at regular intervals (every 2 to 4 weeks) and that if no benefit is perceived, treatment should be discontinued (NICE, 2017a).

Disorders of the gastrointestinal tract may also be treated with local anaesthetic preparations. Lidocaine-containing sprays or ointments can be utilised in the symptomatic treatment of aphthous ulcers and should be applied sparingly as required (NICE, 2017b).

Analgesia for painful haemorrhoids may be achieved with topical local anaesthetics, however, caution is advised due to the potential of sensitisation of the anal skin, and such should only be used for a few days at a time. Lidocaine-containing preparations are preferred, as these preparations are generally very well tolerated, however, local skin reactions can occur, and include burning, itching or irritation (NICE, 2016).

Many of these creams, sprays, gels and ointments are available to purchase without prescriptions over the counter (including those used in the management of minor ailments such as sore throat and haemorrhoids), and so patients may be encouraged to seek advice from a pharmacist in these circumstances.