• Physiological & clinical pain
• Peripheral sensitisation
• Central sensitisation
• Peri-operative pain control
• Therapeutic options

Introduction

In the attempt to unravel the pathophysiological background of pain one needs to differentiate the terms nociception and pain.

Pain relates to the unpleasant or aversive sensation experienced by the individual, whereas nociception relates to the recognition of specific signals in the nervous system. The signals originate in sensory receptors (nociceptors) and provide information related to tissue damage.
Nociceptors that respond to thermal or mechanical stimulation have small diameter, myelinated fibres (Ad type) that transport at high speed (5-30 m/sec) and in humans are known to be related to a sharp pain sensation and are involved in the reflex withdrawal response. Other nociceptors, labelled polymodal nociceptors, can be activated by stimuli of a chemical or intense thermal (hot or cold) or mechanical nature. Signals are transported by afferent fibres (C type fibres) which are unmyelinated and of a small diameter, with a conduction velocity of 0.5-2 m/sec.

Fig. 1: Physiological Pain
In 'physiological' conditions the low-intensity stimulation results in a non-noxious (tactile) stimulus, while the high-intensity stimulus, following activation of the nociceptor and propagation of the signal by separate afferent pathways, may lead to pain. PNS - peripheral nervous system; CNS - central nervous system
From: Woolf and Chong (1993) Anesth Analg 77; 372-379

Upon activation, these C-type fibres will intensify the original stimulus activity and be responsible for the dull, longer-lasting pain.

Fig. 2: Clinical Pain
In a pain state, the change in PNS and CNS processing of the sensory information, and subsequent hyperexcitability, results in low-intensity stimuli now being perceived as painful. PNS - peripheral nervous system; CNS - central nervous system.
From: Woolf and Chong (1993) Anesth Analg 77; 372-379

It is obvious that within pain physiology there is no stable, pre-determined stimulus-response relationship. The final and total response to nociceptor stimulation depends on the intensity and duration of stimulation as well as on the pre-existing state of neural system activity.

From the periphery, the afferent fibres enter into the dorsal horn of the spinal cord where the processing of the signals takes place. Here, the Ad-fibres connect with motor neurons that are responsible for the reflex withdrawal response.
Locally, at the level of the spinal cord, as well as through descending tracts originating from the medulla, modulation and processing of sensory information will take form depending on circumstances and overall level of activity.

Peripheral sensitisation

Next to the primary process initiated with nociceptor activation, the same activation leads to a number of processes that determine the character and intensity of further responses to subsequent stimulation.
Following initial stimulation in the intact, not previously stimulated individual, it is the activation of the high threshold receptors by thermal or mechanical stimuli that lead to pain.

Fig. 3: Peripheral sensitization
Different primary events may create a sensitising environment around the peripheral nerve ending inducing an increased sensitivity thereof. 5-HT - 5 hydroxytryptamine.
From: Woolf and Chong (1993) Anesth Analg 77; 372-379

When the stimulation is prolonged, the response pattern changes. The inflammatory processes accompanying the tissue trauma account for this change, and subsequent sensitisation.
This phenomenon, called peripheral sensitisation is, for a large part, dependent on the release of vasoactive amines from damaged tissue and inflammatory cells, and on the release of neuropeptides released from excited nociceptive nerve endings in the injured area.
These latter peptides further stimulate inflammatory cells to set free a whole spectrum of chemical inflammatory mediators, as a result of which the free nerve endings of the nociceptive afferents are 'bathed' in an environment of different kind of inflammatory mediators. The exposition of the nociceptor to this inflammatory/sensitising environment results in an increased sensitivity of the (originally) high-threshold nociceptors, to now respond to low-intensity stimuli. The consequence of this being that stimulation that was previously perceived as non-painful/innocuous is now resulting in a painful experience.

Central sensitisation

Primary afferents from peripheral nociceptors enter the spinal cord and terminate in specific regions of the dorsal horn, connecting to fibres ascending to higher centres.
Basically afferent fibres terminate on either one of 2 classes of dorsal horn neurons, of which the 'high-threshold nociceptor-specific' neurons respond specifically to noxious stimuli.
Under normal circumstances the so-called 'wide dynamic range' neurons are responsive to non-noxious stimulation, processing this to be perceived as a tactile experience.
When stimulation persists in time, the wide dynamic range neurons become sensitised, leading to hyperresponsiveness. As a consequence, non-noxious stimulation will now result in a painful experience that in duration outlasts the original nociceptive input.
The activated wide dynamic range neurons can be held accountable for the increased sensitivity to mechanical stimulation as well as for the spread of the (hyper)sensitivity of the uninjured tissue surrounding the damaged region.
The increase in spinal excitability will be followed by spatial (receptive field), temporal (duration of stimulus and response) and threshold (sensitivity) increase, together resulting in a hypersensitive and hyperactive state at spinal level.
By an effective prevention of the development of hyperexcitability, a reduction of post-operative pain can be achieved long after the pharmacological duration of action of the analgesic drug.

Fig. 4: Central sensitization
Prolonged exposure to noxious stimulation induce an increased level of sensitivity of the central nervous system and subsequently, low-intensity stimuli may become painful rather then innocuous (or non-painful).
From: Woolf and Chong (1993) Anesth Analg 77; 372-379

Pathophysiology of pain and analgesic therapy - Peri-operative pain control

The negative consequences of pain are multiple in nature but can be grouped under the heading of 'stress-response'. As a consequence of this stress response, and next to the discomfort and impaired welfare of the animal, a number of physiological functions will be impaired. The animals are likely to get into a negative energy balance and research ahs shown that there is clear suppression of the immune status. As a result wound healing will be slowed down, and the incidence of post-surgical complication increases. In the most serious of cases even automutilation is seen.
It can be stated that adequate pain relief promotes the animal's overall wellbeing as well as has a positive effect on the speed and quality of post-surgical recovery.
At the same time, positive aspects such as reduced mobility and weight bearing will be retained since pain treatment at best achieves a state whereby pain is not completely relieved but has become more endurable. Except under conditions of general anaesthesia, full systemic analgesia can not be achieved by administration of analgesic drugs such as opioids or NSAID's.

Fig. 5: Schematic presentation of pain pathway and potential therapeutic options for achieving pain relief.

Therapeutic options

Especially when the demand for pain control concerns analgesia for elective surgical procedures, the importance of an adequate systemic analgesic premedication can not be overestimated.
To achieve this analgesia one can choose between different classes of drugs such as opioids or alpha-2 adrenergic agonists. Both classes of drugs provide a good basis for obtaining surgical analgesia and, together with other anaesthetic drugs, achieving general anaesthesia. Alternatively, one may opt for the use of NSAID's in the anaesthetic protocol to further enhance the quality of analgesia during and post-intervention. It has to be realised thta although NSAID's may certainly provide an extra dimension in analgesia, they can not alone serve to replace either opioids or alpha-2 agents.
Contrary to the above, local anaesthetics can [under specific circumstances] provide adequate or even complete analgesia, when applied in the correct fashion and for the correct indication.

Opioid analgesics

Generally speaking the opioid substances are considered to be the more potent analgesics, although the difference in analgesic potency has been lessened by the introduction of the new and more potent NSAID's. Opioids are widely used for effectively controlling per- and post-operative pain, but their application does potentially cause a range of side-effects. In addition to the induction of analgesia, side-effects include respiratory depression, increased intracranial pressure, and cardiovascular and behavioral effects.
A class differentiation can be made on account of either the specific opioid receptor (mu, kappa, delta and sigma) affinity, or the agonist-antagonist character of the opioids, separating the agonist opioids (like methadone, pethidine and fentanyl), from the mixed agonist/antagonist opioids (like buprenorphine, nalbuphine, pentazocine and butorphanol).
The use of agonist agents (like methadone, fentanyl, or the very potent sufentanil) is primarily limited to its application in neurolept-analgesic anaesthesia. It is then combined with a (major) tranquilizer like droperidol (methadone/droperidol, fentanyl/droperidol - ThalamonalR) or fluanisone (fentanyl/fluanisone - HypnormR), acepromazine (methadone/acepromazine) or midazolam (sufentanil/midazolam) and can produce an adequate anaesthesia in dogs, rodents, and rabbits. Since the duration of action of fentanyl and sufentanil is only limited (± 30 minutes), for prolonged procedures this agent must be repeatedly, or continuously, administered. The longer acting agonist opioids like morphine and methadone are much less potent analgesics than fentanyl and sufentanil, and are more likely to produce respiratory and/or cardiovascular side-effects.

For prolonged pain relief, whether it is following general anaesthesia or not, the mixed agonist/antagonist opioids are commonly used in a wide variety of species. The mixed agonist/antagonist opioid agents (like buprenorphine, nalbuphine, pentazocine and butorphanol) either demonstrate their dual influence on a single type of receptor (i.e. buprenorphine on the mu-receptor) or have an agonistic effect on one, and an antagonistic effect on another type of receptor (i.e. nalbuphine mu-receptor antagonism and kappa-receptor agonism). Their dual character of action makes these agents especially useful in pain control following anaesthesia since their effect combines an antagonism of the agonist-induced sedation and (slight) respiratory impairment, while their agonistic action supplies analgesia. Furthermore, some of these mixed agonist/antagonist opioid drugs are relatively long acting.
Buprenorphine couples a slow onset (30-min) with a duration of action of 8 - 10 hrs and a good analgesic effect with little sedative, cardiovascular or respiratory side-effects. This combination of effects makes it excellently suitable for achieving post-anaesthetic analgesia in the different experimental animal species.
Similar results are obtained with pentazocine and butorphanol although some authors have questioned the quality of analgesia with pentazocine. These agents have a weaker potency and a shorter duration of action (approximately 4 hrs) than buprenorphine.

Alpha-adrenergic agents

The agents from the class of a-2 adrenergic drugs, like xylazine and medetomidine, can be categorized as being sedative/analgesic, and consequently clearly induce a state of sedation together with analgesia.
On account of the sedative/analgesic effect the use of a-2 adrenergic drugs is primarily limited to general anaesthesia in different animal species, where these agents and especially medetomidine, greatly reduce the required dose of any concurrently administered anaesthetic drug. In addition to sedation, drugs from this class produce significant cardiovascular side-effects which include initial hypertension, followed by normo-/hypotension, increased peripheral resistance, a decreased heart rate and cardiac output.

Non-steroidal anti-inflammatory drugs

Another approach to pain relief in the peri-operative period includes the application of Non-Steroidal Anti-Inflammatory Drugs (NSAID's). This class of drugs has traditionally been used in the treatment of chronic, and specifically orthopaedic, pain.
The primary reason that limited the use of the earlier representatives of these drugs pre- and per-operatively was related to its mechanism of action [reduction of prostaglandin synthesis]. The combination of these drugs under conditions of reduced perfusion (as is often seen during anaesthesia) could easily induce serious complications, especially regarding renal function.
Recently, drugs from this class such as carprofen have overcome these objections to the pre- and per-operative application. With their potential for pre-operative use formally recognised, it allows for a truly multimodal design of analgesic therapy. Not only does the per-operative presence of a NSAID contribute to the overall analgesic quality, but at the same time it limits the development of sensitisation of pain system. This latter aspect clearly contributes to limiting post-operative pain and facilitates the achievement of adequate pain control post-surgery.
In contrast to the weak analgesic potency ascribed to the earlier NSAID's, the more recently developed NSAID's like ketoprofen, meloxicam, vedaprofen and carprofen have sufficient analgesic potency to effectively combat post-operative pain. These newer agents might thereby be attractive alternatives for, or additives to, opioids in the post-operative phase, whenever the use of opioids is contra-indicated. In addition, the anti-inflammatory effects of the NSAID's provides for specific indications within the 'pain-control' protocol in the post-surgery period, since inflammation usually develops several hours [to days] after the intervention.

Local analgesics

Although a wide variety of applications of local analgesics in relieving pain in animals can be accrued, the characters of many of our animals prevent the large-scale use of local analgesics as a single anaesthetic agent.
A practically viable form of the use of local analgesics is in combination with sedation/light anaesthesia with the local anaesthetic application or the addition of a local analgesic during general anaesthesia to maximize the alleviation of pain.
Indications such as dental blocks, axillary plexus block or epidural block prior to the intervention in that specific region can be foreseen in companion animal anaesthesia.
Adequate analgesic blockade can be achieved with a single-dose administration of a local analgesic (nerve block, infiltration analgesia), or by way of repeated or continuous administration as with the use of an epidural catheter. An effective local analgesic effect can allow a significant reduction of the anaesthetic depth required or an improved quality of recovery.

Underlying bibliography

• Coderre TJ, Katz J, Vaccarino AL, Melzack R (1993) Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 52; 259-285.
• Hellebrekers, LJ (2000) Pathophysiology of pain in animals and its consequences for analgesic therapy,. In: Animal Pain; A practice-oriented approach to an effective pain control in animals. Hellebrekers LJ Ed, Chapter 5, Van der Wees Publisher, Utrecht, NL.
• Hellebrekers, LJ (2000) Practical analgesic treatment in canine patients. In: Animal Pain; A practice-oriented approach to an effective pain control in animals. Hellebrekers LJ Ed, Chapter 7, Van der Wees Publisher, Utrecht, NL.
• Jessell, TM, Kelly, DD (1991) Pain and analgesia. In: Principles of Neuroscience, 3rd edition, Kandel ER, Schwartz JH and Jessell TM Eds., Chapter 27, Prentice Hall International Corp., London UK
• Lascelles, BDX, Crêpes, PJ, Jones, A, Waterman, AE (1997) Post-operative central hypersensitivity and pain: the pre-emptive value of pethidine for ovariohysterectomie. Pain 73; 461-471
• Lascelles, BDX (2000) Clinical pharmacology of analgesic agents. In: Animal Pain; A practice-oriented approach to an effective pain control in animals. Hellebrekers LJ Ed, Chapter 6, Van der Wees Publisher, Utrecht, NL.
• Mathews, KA (2000) Management of pain in cats. In: Animal Pain; A practice-oriented approach to an effective pain control in animals. Hellebrekers LJ Ed, Chapter 8, Van der Wees Publisher, Utrecht, NL.
• O'Connor TC, Abram, SE (1995) Inhibition of nociception-induced spinal sensitization by anesthetic agents. Anesthesiology 82; 259-266
• Sidle PJ, Cousins MJ (1998) Introduction to pain mechanisms: Implications for Neural Blockade. In: Neural blockade in clinical anaesthesia and management of pain, 3rd edition, Cousins, MJ and Bridenbaugh PO Eds., Chapter 23.1, Lippincott-Raven Publishers, New York, USA
• Woolf, CJ, Chong MS (1993) Pre-emptive analgesia- Treating post-operative pain by preventing the establishment of central sensitization. Ernest Analg 77; 372-379
• Yashpal K, Katz J, Coderre, TJ (1996) Effects of pre-emptive or postinjury intrathecal local anesthesia on persistent nociceptive responses in rats. Anesthesiology 84; 1119-1128