Symptomatic orthopedic pain therapy concentrates on nociception in bones, muscles, tendons, and joints after the pain stimulus has already acted on the body. This means that the nociceptive process has already started. Nociceptors have been irritated, and the pain signals have been transmitted to the brain via the afferent fibers and the spinal cord. Pain has already been perceived in the brain, and the motor and autonomic reactions in the periphery have been initiated. Symptomatic pain therapy acts on the different areas responsible for the transmission and perception of pain, and the reaction to it, with the emphasis varying according to the individual type of treatment (Fig. 4.1).
In symptomatic pain therapy, unlike causal pain therapy, the physician and patient expect an immediate response. Thus, fast-working analgesics, local injections, physical agents, and directly acting forms of electrotherapy constitute the main focus of treatment.
In many cases, patients apply soothing warmth before consulting a doctor. Heat acts as a local analgesic, removing inflammatory mediators, relaxing muscles, and calming the autonomic nervous system. The cortex and the psyche perceive heat as being pleasant (Fig. 4.2).
Heat can be applied in different ways. It can be transmitted either by placing the heat carrier in direct contact with the patient or indirectly by using radiant heat. The heat from fango (volcanic mud used in spa treatments) and mud packs penetrates well into the skin. The simple application of dry heat, e.g., various forms of infrared treatment, has also proven effective in practice. Heat pads, hot water bottles, and hot baths are immediate measures which are recommended for home treatment. The local thermal effects, in increasing order (Tilscher and Eder 1989), are as follows:
Special forms of massage include reflex zone massage and connective tissue massage. The connective tissue massage technique involves a specific way of stroking with a fingertip (usually the third or fourth finger), with the hand, arm, and shoulder held in a relaxed position. The direction of the strokes is segmentally orientated.
It is important that the patient is placed in a comfortable and relaxed position during all types of massage. This particularly applies to the affected body part. Massage acts positively on local nociception by removing inflammatory mediators. In addition, the vicious cycle of pain–muscle-cramping–pain is disrupted at the muscular level (Fig. 4.3).
High-frequency currents in the form of short waves, decimeter waves, and microwave therapy act by warming the depths of the tissue being treated. The oscillations are too fast to excite cells directly. The high-frequency currents that are applied therapeutically start at 20,000 Hz, increase to the diathermic ranges of about 3 × 106 Hz, and go up to the short-wave therapeutic range at about 5×107 Hz.
Low-frequency currents (15–250 Hz) are used in galvanization, where direct current is applied. In this frequency range, an increase in polarization or depolarization is found in the cells, with all transitional stages. A pain-relieving effect has been attributed to the constantly flowing direct current (e.g., in the form of a hydroelectric bath). Bernard’s diadynamic currents are low-frequency currents with alternating frequency and amplitude, which also act to relieve pain. The electric currents are usually applied bipolarly, i.e., using two electrodes.
Midfrequency currents are sinusoidal alternating currents with frequencies between 1 and 1,000 Hz. The principle of midfrequency or interferential current treatment involves the production of biologically effective frequency ranges within the organism itself. In interferential treatment, two biologically nonirritant midfrequency currents (e.g., 4,000 Hz) are applied to the body using two electrodes. The frequency of the currents differs by up to 100 Hz. Their superposition results in the development of an amplitude- and frequency-modulated current with lower effective frequency, i.e., a frequency that is biologically effective within the body. The advantages of interferential treatment are twofold: the midfrequency stimulating current effectively overcomes the pain-sensitive skin and outer tissue layers, while the low-frequency currents (between 0 and 100 Hz) are first generated in the deeper tissue layers and function there as a form of pain therapy. In this way, electrical currents that cannot be applied directly from external sources at this frequency and intensity are developed at the desired location within the body. The direct action of the low-frequency current in the deeper tissue affects the autonomic nervous system and improves blood flow.
The word acupuncture comes from the Latin acus, “needle,” and pungere, “to prick.” Both traditional and classical Chinese medicine use a technique known as zhën jiŭ (= insertion and burning, referring to acupuncture together with moxibustion). Fine needles are inserted into specific points on the body. The Chinese term for these acupuncture points is shu xue, where shu means transporting or conducting, and xue means cavity or hole, because in the area of an acupuncture point there is generally a hole in the fascia through which a nerve, vein, or artery exits.
According to Heine (1987), approximately 80% of the traditional acupuncture points have an anatomical counterpart. Morphologically they can be described as perforations of the superficial body fascia tissue by a bundle of blood vessels and nerves.
The analgesic effect of acupuncture is probably due to the release of endorphins, which ease pain. According to Pomeranz (1981), the peripheral pain stimulus activates the analgesic action. This gives rise to a mechanism that acts in three stages. The pain caused by the needle prick acts as a noxious stimulus (1 in Fig. 4.6), stimulating the nociceptor (2). The pain signals are then further transmitted to the posterior horn of the spinal cord (4) via the afferent fibers (3). It is here that the pain signals are transferred to a second neuron, which in turn transmits the pain signals up to the thalamus and finally to the cortex (5), the place where pain is localized. The body’s own opioid peptides (endorphins) inhibit the transmission of nociceptive information, acting on the synapses of the nociceptive system in the spinal cord (4) and the brain (5). Endogenous opioids are released as inhibitory transmitters from the neurons. These neurons can be thought of as part of the antinociceptive system that is activated by acupuncture (Stux et al 1993).
Fig. 4.6 Acupuncture and nociception. The pinprick from acupuncture acts as a noxious stimulus (1), stimulating the nociceptor (2). The stimulus is transmitted to the spinal cord (4) via the afferent fibers (3) and from there via the spinothalamic tract to the brainstem (5). Pain is not perceived. Pain-inhibiting mechanisms are sent to the periphery via the descending pathways and act as an analgesic.
The classic body acupuncture can be used to treat all forms of chronic pain, acting as an adjuvant form of treatment within orthopedic pain therapy. The treatment should preferably be performed in a stress-relieving position, i.e., with the spine relaxed (Fig. 4.7).
Fig. 4.7 Acupuncture program, e.g., for sciatica. The patient lies relaxed on one side with hips and knees slightly bent. The painful side is uppermost. The needles are inserted one after the other, starting with the foot. The needles are inserted between 5 and 15 mm deep and are removed after 20 minutes. The acupuncture points are essentially found in the areas of pain or radiation.
We have assessed pain patients during a comparative study on the effectiveness of acupuncture within the scope of pain therapy. In this study, acupuncture points were not individually chosen, but were rather based on standardized points for needle insertion (Grifka and Schleuß 1995). The study established that acupuncture using the traditional acupuncture points is significantly more effective than placebo acupuncture, where points were randomly chosen. The reported values for the total amount of pain and the highest level of pain were significantly lower for patients treated with traditional acupuncture over 14 treatment sessions than for patients treated with placebo acupuncture (Grifka and Schleuß 1995). However, the attitude of individual patients to the effectiveness of acupuncture plays an important role (Grabow 1992).
It is possible to treat the primary disorder by injecting fluids with anesthetic, anti-inflammatory, and antiedemic properties directly into the nociceptive source in the spine (Fig. 4.8). This avoids loading the entire body with more medication than necessary.
Fig. 4.8 The influence of TLIT on the nociception in the musculoskeletal system. The nociceptors and afferent fibers are switched off using local infiltration or nerve blocks (2 and 3). The nociception–muscle tension–adaptive posture cycle (2, 3, 6, 1a) is disrupted by the use of therapeutic local infiltration into tendon attachments and muscle infiltration. The autonomic reaction (7) is switched off using sympathetic chain blocks.
The patient’s medical history and the results of manual medicine examinations provide important clues to the choice of site for the local therapeutic injection (see Chapter 2, “Medical History,” “Clinical Examination”, and “Neurological–Orthopedic Examination”). Further guidance can be obtained from diagnostic local anesthesia or local pain provocation using saline solutions or contrast agents (see Chapter 2, “Trial Measures for the Diagnosis of Pain”).
Local anesthetics, steroids, or a combination of the two are used for the therapeutic local injection, depending on the aim of the treatment. Pure saline solution is also sometimes used: the hypertonic solution has an osmotic effect on the edemic tissue and dilutes the accumulated inflammatory mediators.
Therapeutic local anesthesia (TLA) is a fundamental part of the TLIT. A few milliliters of dilute (0.5–1.5%) local anesthetic solution are all that is needed to switch off sensitized nociceptors and nerve fibers that have developed into nociceptors. This results in the following effects:
Nociceptors and afferent fibers are reversibly switched off after local anesthetics have infiltrated the tissue. This abolishes the excitability of pain transmission, sensitive end organs, and the ability of sensitive sections of nerve fibers to transmit signals, and does so in a reversible manner at a local level. The effectiveness of local anesthesia decreases as nerve fiber diameter increases. For this reason, sensitive nerves are initially blocked and motor nerve fibers are blocked when high doses are injected. TLA is directed toward the sensitive nerve fibers. Local anesthetics reduce the permeability of the membrane to cations, especially sodium ions. This results in diminished membrane permeability with reduced levels of excitability.
Neurophysiologically based TLA measures break the link between muscle tension and the excitation of nociceptors (Zimmermann 1993). A nociceptor or nerve block results in a reduction in pain and nerve excitability and an increase in local blood flow for a period of 3 to 8 hours, depending on how long the applied local anesthetic works effectively. Experience shows that the pain-relieving effect is maintained longer than would be expected from the local anesthetic’s duration of action. This is especially the case with repeated administration. The state of reduced excitability continues, so that it is possible to obtain a permanent effect with a series of 8 to 12 infiltrations on consecutive days.
Infiltrating a local anesthetic multiple times into the area of nociception and the outgoing afferent fibers results in a desensitization of overactive neural elements. The frequency and intensity of the transmitted excitatory impulses that are required for pain perception and motor or autonomic reactions decline.
Repeated administration of TLA prevents the development of pain chronification (Fig. 4.9).
Fig. 4.9 The reduction in the excitability of nociceptors and afferent fibers by repeated use (8–12 times) of therapeutic local anesthesia. The irritation thresholds of nociceptors and afferent fibers, which have been raised by the repeated pain stimuli, revert to their normal level. The additional use of electrotherapy with positioning, physical therapy, and heat treatment further strengthens this effect.
If chronification has already set in, the use of repeated TLA disrupts the vicious circle of adaptive posture–nerve irritation–increased muscle tension and pain at the neural level. The desensitization of nociceptors and afferent fibers, with an increase in irritation thresholds, leads to the same mechanical stimuli causing less pain. In this phase, causal pain therapy has to be implemented by relieving positioning, exercises, etc. In chronic spinal pain syndromes, the repeated use of TLA in the area of nociception and afferent fibers results in a reduction in pain perception and pain processing (Zieglgänsberger 1986).
Rydevik’s (1990) and Olmarker and Rydevik’s (1993) groups studied the reactive inflammatory changes in nerves and nerve roots (e.g., due to prolapsed intervertebral disk tissue). They demonstrated that a defined chronic compression evokes an inflammatory and edematous change in the nerve root. This change can be largely prevented by the use of lidocaine injections (Yabuki et al 1996).
Most local anesthetics also act as vasodilators, so blood flow increases markedly in the infiltrated area. However, this also means that injected medication is more rapidly removed by the circulatory system. In most cases, however, there is no indication for the addition of vasoconstrictors to the local injection treatment used for spinal symptoms. Notable specific side effects of the administration of local anesthetics are cardiovascular complications when the blood levels are too high, and allergic reactions. These complications are rare, however.
Bupivacaine (0.25%) is lipophilic and is preferably used as a long-term anesthetic. When used at concentrations of up to 0.25%, it results in long-lasting analgesia, with motor activity remaining largely unaffected.
Steroids are also infiltrated initially and during further treatment with local injections, as part of orthopedic pain therapy. The treatment focuses on the concomitant inflammatory reaction in the nociceptors and the area surrounding the afferent fibers. Steroids neutralize the pain-evoking prostaglandins and leukotrienes (Wehling 1993). For this reason, they have a local analgesic effect in addition to their anti-inflammatory action. The use of steroids with a high receptor affinity, such as triamcinolone, is preferable. A sufficiently high concentration of active ingredients in the immediate proximity of irritated structures is needed to ensure an effective pharmacodynamic interaction of steroids with the circumscribed inflammatory processes. The use of general medication such as orally administered steroids is therefore not a part of orthopedic pain therapy and is used only in exceptional cases. The concentration of steroid at the source of pain should be maintained for an extended period. At the same time, the systemic perfusion of glucocorticoids should be kept to a minimum in order to limit the pharmacodynamic loading on the entire organism. These guidelines can best be followed by using glucocorticoid depot preparations in the form of crystal suspensions. We therefore mainly use triamcinolone diacetate and triamcinolone acetonide when treating acute and chronic radiculopathies. Our research (Barth et al 1990) has demonstrated that local administration of 5 to 10 mg of these steroids can saturate all steroid receptors in the surrounding tissues. Significant side effects (e.g., a sustained suppression of the body’s own cortisol production) are not to be expected when the steroid is administered in this form one to three times as part of a treatment cycle for a pain syndrome. Allergic reactions to carrier substances in steroids and local anesthetics are, however, to be anticipated when using all types of medication (see Chapter 10).
Therapeutic local injections are administered to painful muscle and tendon insertions as well as to different locations in the vertebral motor segments. The indications and techniques for individual injections can be found in the atlas section of this book (see Chapter 5, “Nociception and the Distribution of Pain Signals in the Spine”).
As early as the 1920s, in connection with research into tuberculosis, there were already speculations that special proteins act as messengers in “cell communication” (Zinsser and Tamiya 1926). Since then, a succession of new proteins has been characterized and increasingly complex networks of messengers have been discovered, initially with inconsistent nomenclature. In 1991, all mediators were for the first time grouped together under the term cytokines, and a systematic naming system was introduced (Klein 1991).
Interleukin 1 (IL-1) was first described in 1940, under the name “endogenous pyrogen.” It was subsequently found that this protein can be detected in all cells of the body, and that IL-1 receptors exist (Dower et al 1984).When the biological actions of IL-1 were studied, it was found to significantly participate in the genesis and maintenance of acute and chronic inflammation as well as in the destruction of tissue. The nerve root, along with the articular cartilage, is an important target tissue in this context. In nerve root compression syndrome, pain mediators, IL-1 in particular, are released at the nerve root coursing there and cause a local inflammatory process.
Interleukin-1 receptor antagonist protein (IL-1Ra) is the only naturally occurring antagonist so far discovered within the cytokine family (Liao et al 1984). More precise studies and experiments were able to demonstrate that a disproportionate ratio between agonist and antagonist seemed to govern certain disorders (Lennard 1995).
As it acts by binding to the IL-1 receptor, the competitive binding of receptors seems to play a decisive role in pathology. An excess of IL-1Ra has to be present to repress IL-1 enough to antagonize its biological actions (Arend et al 1990; Seckinger et al 1990). This is the starting point for Orthokine therapy using anti-inflammatory substances in the form of autologous IL-1Ra, which have an anti-inflammatory effect, are antiedemic, and are pain relieving.
Human IL-1Ra has also been successfully cloned. Recombinant IL-1Ra has been successfully applied experimentally and in the treatment of rheumatism, where it has been used as a systemic treatment by means of subcutaneous injection (Carter et al 1990; Arend et al 1991b; Smith and Arnett 1991; Campion et al 1996; Bresnihan et al 1998).
Recombinant IL-1Ra has, however, several disadvantages in comparison to the autologous substance. The glycosylation of the protein varies between individuals, and it appears that higher surplus concentrations of the recombinant version are needed to repress the IL-1 at the receptor. In addition, a reaction occurring at the point of needle insertion has frequently been observed (Antin et al 1994; Bresnihan et al 1998). Finally, as the human DNA is combined with additives, the possibility of potential allergic reactions should be considered.
It is possible to manufacture autologous IL-1Ra using the EOT technique. To this end, a special technique is used to prepare the patient’s own blood and apply it in the form of an autologous conditioned serum with a spinal injection (Fig. 4.10, Fig. 4.11, Fig. 4.12, Fig. 4.13, Fig. 4.14, Fig. 4.15, Fig. 4.16, Fig. 4.17, Fig. 4.18).
Fig. 4.13 The blood-filled tubes are centrifuged at 5,000 rpm for 10 minutes to separate the protein-containing serum from the cruor. Care must be taken to distribute the tubes evenly when loading the centrifuge.
Fig. 4.15 The IL-1Ra-enriched serum is then extracted sterilely using two conventional 2 or 5 mL Luer-Lok syringes, each containing 1–2 mL without solid blood components. Different coloring of the serum can be explained by individual blood components such as triglycerides, cholesterol, and proteins or by blood sampling and processing factors such as hemolysis. The coloring has no impact on efficacy.
Fig. 4.17 In most cases, material for four spinal injections can be collected with two EOT tubes. The Orthokine injection syringes are labeled and stored in a cool place in special Orthokine cartons at –18°C. A supplementary entry is then made in the Orthokine laboratory notebook along with the processing date, time, number of serum syringes collected, and the expiration date. The specimens have a shelf life of 7 months.
Fig. 4.18 Epidural perineural injection of the thawed Orthokine using the dual-needle system and a syringe filter (see Chapter 9). Depending on the ambient temperature, the thawing process requires approximately 20–30 minutes. For this spinal injection, 1–2 mL Orthokine is required.
It is known that natural IL-1 and IL-1Ra occur to a greater extent in the monocytes of the human blood. It was also proven that certain surface structures stimulate the production and distribution of IL-1Ra. When preparing the patient’s blood, the property of the glass beads contained in the Orthokine syringe or EOT syringe with their special surface structure is used to stimulate the monocytes to produce larger quantities of IL-1Ra.Thus, after an incubation period of 6 to 9 hours at 37°C (Fig. 4.12), a concentrate of autologous conditioned serum enriched with IL-1Ra develops that is centrifuged and then extracted sterilely and frozen (Fig. 4.13, Fig. 4.14, Fig. 4.15, Fig. 4.16). With the injection of the autologous concentrate from IL-1Ra, the inflammatory process at the nerve root (Fig. 4.18) can therefore counteract the cause of the pain. It can be assumed that the less the initial damage is, the longer the effect will last.
In medical terms, Orthokine therapy can be repeated as often as necessary if it works well and the effect is long-lasting. The injection intervals are based on the individual outpatient or inpatient treatment plan, depending on the disease presentation and the severity of the symptoms.
Orthokine has been used for several years in the treatment of intervertebral disk pathologies and nerve root irritation. Nerve irritation syndromes can be effectively treated with the specific administration of medication at the nerve root in the form of a nerve root block and epidural administration. Intradiscal administration, where indicated, is also appropriate. In addition, Orthokine can be successfully injected into arthrotically altered facet joints. Further statements are expected following the completion of clinical studies that are currently in progress. Orthokine is approved in the European Union and in Australia.
When using Orthokine, the usual contraindications for injections apply. Injections may not be made in areas with skin lesions or general skin diseases such as eczema. Fever and general infections are also contraindications. It is also important that the patient does not have an infection at the time of the initial blood sampling, because this can lead to a stronger production of proinflammatory cytokines in the blood taken.
Compared to the cortisone and analgesic preparations commonly used during injections near the spine, Orthokine has nearly no side effects. Especially patients with back pain with recurrent symptom peaks undergo repeated injections and can benefit from an alternative therapy that is nearly free of adverse effects. This is particularly interesting for patients in whom cortisone can be used to only a limited extent, such as patients with diabetes or cardiovascular diseases, e.g., labile arterial hypertension. Orthokine does not increase blood glucose or blood pressure and does not cause any gastrointestinal discomfort.
Fig. 4.19a–f shows the original documentation of a male patient with insulin-requiring diabetes and blood glucose regulation with an insulin pump who underwent, inter alia, treatment with spinal injections for a spinal syndrome. The patient was given both a cortisone injection (triamcinolone 10 mg) and an Orthokine injection. As can be seen from the documentation log of the insulin pump and the patient’s remarks, one low-dosage cortisone dose (triamcinolone 10 mg) as a periarticular facet infiltration already led to pronounced blood glucose fluctuations (Fig. 4.19a–d) that clearly complicated insulin adjustment and, in turn, created a very high risk of hypoglycemia.
Fig. 4.19 (a) Graph documentation of the insulin pump of a male patient after one-time lumbar facet infiltration with 10-mg triamcinolone acetonide on March 28, 2011. The blood glucose reached levels of over 400 mg/dL at some points (April 2, 2011).
Fig. 4.19 (b) Tabular overview of the graph documentation presented in Fig. 4.19a with precise indication of day, time, and blood glucose along with the patient’s remarks about the adjustment of the insulin bolus doses after one-time cortisone injection (March 28, 2011).
Fig. 4.19 (c) Overall overview (demand bolus doses/basal insulin dose) of the insulin pump of the same patient (Fig. 4.19a, b). The insulin bolus rates provided in addition to the ongoing basal insulin dose are more frequent than usual in the period following the cortisone injection (March 28, 2011).
Fig. 4.19 (d) Same patient’s own notes (Fig. 4.19a–c). Altogether both the average blood glucose level and the average insulin volume were strongly elevated in the week following the cortisone injection (March 28, 2011). The insulin adjustment was markedly extended with an increased risk of hypoglycemia.
Fig. 4.19 (e) Graph documentation of the patient (Fig. 4.19a–d) in an injection-free interval. The blood glucose levels were not higher than average.
Fig. 4.19 (f) Graph documentation of the same patient after one-time lumbar facet infiltration with Orthokine on May 18, 2011. In contrast to the blood glucose trend after the cortisone injection on March 28, 2011 (Fig. 4.19a, b), here a markedly more harmoniously blood glucose trend can be observed, comparable to the trend in the injection-free interval (Fig. 4.19e).
Systemic adverse effects on the Orthokine itself in the form of allergic reactions are not known. The patient is advised to avoid activities involving physical exertion on the day of the injection, such as participating in sports or using a sauna.
Many clinical studies have established the effectiveness of various active ingredients administered in the epidural perineural injection treatment of lumbar nerve root compression syndromes (Carette et al 1997; Krämer et al 1997a). So far, only one clinical study has assessed the effectiveness of IL-1Ra-enriched serum compared with triamcinolone in this type of treatment (Becker et al 2007). In this prospective randomized double-blind study of 90 patients, 5 and 10 mg of autologous IL-1Ra were compared with triamcinolone under identical test conditions. Measurements were made at six follow-up sessions, at 6-monthly intervals. These patients suffered from MRI-verified lumbar nerve root compression symptoms where surgical intervention was not indicated. Further therapy, except oral PRN medication, was not permitted during the follow-up period. The treatment effect was recorded using a standardized clinical examination and questionnaires (Short Form -36 [SF-36], SES, visual analogue scale [VAS], Oswestry Score, pain diary). The effectiveness of therapy was assessed over the entire examination period by means of general linear models. All groups demonstrated a significant improvement in their symptoms. The assessment of the differences between the groups over a period of time showed, for example, a significant difference in pain levels (p < 0.05) after 3 months when measured with the VAS. The IL-1Ra group experienced a lasting reduction in pain, while the triamcinolone group tended toward a further increase in pain.
Serum enriched with IL-1Ra (e.g., Orthokine) offers an alternative form of therapy for the treatment of nerve root compression syndromes. When the diagnosis has been correctly made, a significant improvement in symptoms can be achieved over an average period of 3 to 6 months. It has additionally been proven that the epidural perineural application involves minimal risk and that systemic side effects do not occur.
An understanding of nociception and its regulatory systems is important in planning and conducting multimodal medication concomitant therapy for the treatment of spinal disorders (see Chapter 1, “Nociception and Chronification”). From the triggering of the stimulus in the periphery to the final perception of pain in the cortex, pain can be modulated and repressed by medication that acts specifically on the individual systems.
The cyclooxygenase system is important in nociception, and cyclooxygenase inhibitors are administered predominantly in the periphery. In contrast, opioids bind to specific receptors in the central nervous system (CNS). Opioids can also act on peripheral opioid receptors that have been either newly generated in tissue altered by inflammation or placed in a functional standby mode. It therefore makes sense to administer opioids as a regional analgesic, e.g., intra-articularly.
The transmission of a nociceptive signals originating in the periphery is linked to the function of A5- and C-fibers. Signal transmission takes place via polarization and rapid sodium influx into the cells. Depending on the dose administered, local anesthetics prevent this transmission of signals to a certain extent, up to and including a complete nerve block. The transmission of nociceptive signals to the first interneuron at the spinal cord level is associated with many regulatory processes. Cell excitation is transmitted by the release of excitatory transmitters such as substance P, calcitonin gene-related peptide, glutamate, or neurokinin. A variety of filtering and modulating processes act on the pain impulse when it is transmitted from the first afferent neuron to the second neuron. Descending mechanisms for pain inhibition and inhibiting neurotransmitters such as endorphin and enkephalin play an important role here. Pain stimuli that are especially strong or long-lasting can cause permanent cellular changes at the spinal cord level (“neuroplasticity”) so that a permanent increase in perceived pain can take place in certain cases. These sensitization processes occur especially when the so-called N-methyl-D-aspartate (NMDA) receptor channels are opened as a result of the repeated excitation of spinal cord neurons and an increase in calcium influx takes place. NMDA receptor antagonists,such as ketamine, influence spinal sensitization even in small doses.
Opioids bind to μ- or δ-receptors at the spinal cord level, causing a reduction in calcium influx and an increase in the dose-dependent polarization wave in nociceptive interneurons. Inhibition of nociception in the spinal cord also takes place as a result of the action of α-2 agonists (clonidine), GABA-B agonists, and 5-HT agonists (serotonin).
It therefore makes sense in the clinical environment to combine different medications (e.g., cyclooxygenase inhibitors, opioids, local anesthetics, α-2 agonists, NMDA receptor antagonists) as part of a multimodal medication concomitant therapy. In addition to this list are the adjuvant analgesics; these are not pain medication as such, but because of their special characteristics they are able to reduce the amount of analgesics required and thus minimize the sometimes considerable side effects.
To record the pathophysiological cause of pain, it is essential to take an accurate individual pain history. This includes pain intensity when resting and when weight-bearing, the location of pain and area of spread, the quality of pain, the behavior of symptoms over a 24-hour period, and the subjective assessment of pain-aggravating and pain-relieving activities. Knowledge of all these factors is essential when creating a multimodal medication therapy plan, to do the individual circumstances and characteristics justice.
First, it has to be decided if the nociceptive pain has a somatic or visceral genesis, or if the pain is neuropathic (see Chapter 1, “Nociception and Chronification”). Neuropathic pain can be found in the peripheral nerve–conducting channels or in the CNS. In so-called psychogenic pain, in the form of a somatoform pain disorder, the pain is influenced by serious psychosocial factors.
The information acquired from the medical history regarding the quality of pain (e.g., clear, burning, stabbing, shooting, deep, dull, or gnawing) gives clues as to which pharmaceutical adjuvant analgesics are the most suitable (e.g., antidepressants, anticonvulsants, glucocorticoids). The behavior of pain symptoms over a 24 hour period governs, for example, whether a higher dose is needed during the day or at night. The activities that subjectively influence the pain must not be neglected. Most patients tend to find their own way of dealing with the pain over the course of the illness. It is imperative to question patients about the type of coping strategies they use and to support these strategies when appropriate. Physical measures, such as heat, cold, or certain positions or postures, can play an important role in the reduction of pain medication.
Thorough pain measurements, their documentation, and the precise taking of the pain history provide a further basis for efficient pain therapy. The estimation of pain intensity is always subjective, except with young children or demented or nonresponsive patients where it relies on third-party observation. A variety of validated instruments are available for reporting pain intensity. The VAS measures the intensity of pain on a straight line labeled “no pain” at one end and “worst pain imaginable” at the other. The patient marks the line at the point best representing the pain intensity and this is then read off a scale from 0 to 100 on the other side of the paper (Fig. 4.20a). The numeric rating scale (NRS) involves patients numerically rating their pain, e.g., 0 = no pain, 5 = moderate pain, and 10 = unbearable pain (Fig. 4.20b). Some patients, especially elderly people, find the verbal rating scale (VRS) (Fig. 4.20c) easier to use. The patient chooses between verbal items such as:
While the WHO analgesic ladder was developed for tumor patients, with specific deviations/variations it is also suitable for every type of pharmaceutical pain therapy, whether the pain is acute or chronic (Fig. 4.21).
Nonopioids in combination with adjuvant medication are used at level I. Level II involves the combination of mild opioids with nonopioids and adjuvant medication. For severe pain (level III), the administration of strong opioids together with nonopioids and adjuvant medication is required.
For the treatment of chronic pain, the WHO analgesic ladder additionally recommends that medication should, if possible, be administered noninvasively, in doses tailored to the individual patient, and at specific times (“by the clock”) rather than “on demand” (PRN).
In most cases, the action of nonopioid analgesics is based on the inhibition of cyclooxygenase and thus of prostaglandins. The prostaglandins dilate capillaries and so amplify the reaction to chemical, mechanical, and thermal stimuli, facilitating inflammation and causing hyperalgesia. Prostaglandins also have important physiological functions, such as the regulation of blood flow in the kidneys, the tubular transport of sodium and water, and the formation of gastric mucus.
NSAIDs and coxibs act not only as antipyretics and analgesics, but also as anti-inflammatories, by enriching the acidic inflamed environment. However, they also accumulate in “acidic” organs such as the stomach or kidneys, with the corresponding adverse effects. Their use is therefore indicated only in acute inflammatory processes because of their serious side effects.
By the end of the 1970s, it was recognized that aspirin and other similar substances inhibit the synthesis of prostaglandin. Traumatic or inflammatory tissue damage results in the release of inflammatory mediators such as prostaglandin, histamine, and bradykinin. Each substance is inactive on its own, but when combined they cause strong pain reactions (Waldvogel 2001). It is at this point that NSAIDs act (Fig. 4.22), and by the end of the 1970s, it was recognized that aspirin and other similar substances inhibit the synthesis of prostaglandin.
The administration of cyclooxygenase inhibitors affects metabolic pathways so that less prostaglandin, prostacyclin, and thromboxane are produced. This in turn causes an increase in the accumulation of bronchoconstrictive leukotrienes, which explains the provocation of allergic attacks in predisposed individuals. The lack of thromboxane causes the aggregation of thrombocytes to be delayed for about 3 to 4 days until new blood platelets have been formed. The inhibition of the regulatory function of the prostaglandin PGE-2 in the gastric mucosa can cause ulceration, sometimes resulting in severe gastrointestinal bleeding that may even be fatal. Prostaglandins further affect the renin–aldosterone system and control the renal blood flow and the glomerular filtration rate (Fig. 4.23).
The use of NSAIDs in combination with other medication can also lead to problems, as a multitude of drug interactions can occur. This should be kept in mind when treating patients who take several drugs (Table 4.3, Table 4.4).
There are two isozymes of cyclooxygenase, COX-1 and COX-2. COX-1 is thought to be responsible for gastric protection, renal homeostasis, and the aggregation of platelets, while COX-2 is linked to inflammation, fever, and pain (Fig. 4.24). COX-2 has also been shown to play a significant role in the functioning of tissues and organs including brain, kidneys, ovaries, uterus, and endothelium.
The initial euphoria associated with the development of selective COX-2 inhibitors soon vanished, in the light of cumulative clinical experience and more recent research results. According to the U.S. Food and Drug Administration in July 2002, long-term results with celecoxib (Celebrex) demonstrated no improvement in the gastrointestinal complication profile compared with substances such as ibuprofen or diclofenac. Further studies have shown that the long-term use of COX-2 inhibitors, in particular high doses of rofecoxib (Vioxx 50), results in a significant increase in the incidence of myocardial infarction and thromboembolic episodes.Ott et al (2003) showed in their study that the use of valdecoxib (Bextra) and parecoxib leads to a short-term significant increase in infarction and stroke risk in high-risk patients following coronary surgery. However, further studies at the end of 2004 proved that the long-term use of common NSAIDs such as naproxen can likewise play a role in the increased rates of heart attack. This is associated with substance-specific characteristics: etoricoxib affects kidney function and blood pressure more in the long term and is therefore contraindicated in patients with blood pressure problems. Ulcers that are already present heal more poorly when patients are taking coxibs than when they are being treated with conventional NSAIDs. However, COX-2 inhibitors do have advantages in certain situations, such as in the presence of blood coagulation problems or known pseudoallergic bronchoconstrictive reactions to NSAIDs. In general, neither NSAIDs nor coxibs are suitable medications for long-term therapy but rather are indicated solely in the acute inflammatory phase!
Metamizole,a broad-spectrum nonopioid analgesic, is the most important representative of this substance group in clinical practice. It has analgesic, antipyretic, and spasmolytic properties, and acts both peripherally and centrally.
The use of metamizole has experienced many up and downs in the past. Its side effects can be serious. In addition to the danger of a massive drop in blood pressure, leading to shock-like conditions when it is injected intravenously too rapidly (boluses require caution), the potentially fatal but seldom observed complication of agranulocytosis is feared. According to the International Agranulocytosis and Aplastic Study (IAAAS), the risk of developing agranulocytosis is estimated to be 1:1 million weeks of use (Kaufmann et al 1986, 1991). More recent data from the Netherlands and Poland confirm these results (van der Klauw et al 1999; Maj and Lis 2002). In 2002, a Swedish study (Hedenmalm and Spigset 2002) found a considerably higher risk (1:10,000). This paper led to renewed discussions and the withdrawal of the drug from the market in some European countries. The higher risk was contradicted by the meta-analysis of Andrade et al (1998) in which the life-threatening complications related to the intake of different nonopioids were compared. According to this analysis, the estimated rate of fatal episodes was 185:1 million for aspirin, 592:1 million for diclofenac, 20:1 million for paracetamol, and 25:1 million for metamizole. Ibáñez et al (2005) then confirmed the IAAAS statistics, but found a connection between the dosage level and the duration of treatment. Ibáñez and colleagues came to the conclusion that in Germany the risk of agranulocytosis resulting from the administration of metamizole is very rare, and that the use of metamizole makes sense when the risk of complications with other nonopioids is taken into account. It is, however, important to note that the disposition to the development of agranulocytosis is genetically determined and that certain populations clearly react more sensitively than others. In this context, it is especially important to recognize agranulocytosis in time, with its symptoms of high fever, ulcerous lesions in the mouth and pharynx, changes in blood count, and, more rarely, pneumonia and sepsis. The medication should immediately be stopped while these conditions are still reversible.
Paracetamol is the only aniline derivative on the market. Its mechanism of action has not yet been fully explained. It is currently postulated that there is a third form of cyclooxygenase (COX-3) that is mainly created in the CNS and is selectively inhibited by paracetamol. This could explain paracetamol’s central analgesic action. In addition, its action on the central enzymatic NO synthesis and the serotonergic system has been proven.
Paracetamol can be administered to infants and during breastfeeding. The severe and, at times, fatal complication of liver cell necrosis has to be mentioned. This occurs as a result of overdose (more than 6 g daily over a long period of time) or glutathione deficiency (e.g., due to cachexia or preexisting liver function disorders) and can also occur at normal dosages. In Germany, paracetamol overdose is currently the most frequent reason for acute liver failure (including 50% accidental intoxication; Canbay et al 2009). N-acetylcysteine is administered as the antidote (Fig. 4.25).
When the toxic limits of oral and especially rectal administration are taken into account, the plasma levels of paracetamol are not high enough to result in an analgesic effect, particularly in infants and young children. For this reason, the introduction of intravenously administered paracetamol has been welcomed in Germany. Its use enables an efficient plasma level to be reached while still keeping within the maximum daily dosage. It is important to note the short infusion time (maximum 15 minutes) needed to reach the desired plasma levels.
To the best of our current knowledge, flupirtine acts by enhancing the activity of the descending pain-inhibiting pathways. The serotonergic system also seems to be involved. Flupirtine acts additionally as a muscle relaxant and is said to interact with NMDA receptors. What this means in the prevention of chronification is under discussion, but conclusive evidence is not yet available. Documented case studies and research into chronic pain have not yet provided sufficient information, especially as flupirtine is not approved for long-term therapy because of its severe cholestatic complications,which should not be ignored.
Opiate receptors are known to be present in the CNS, particularly in the limbic system, the medulla oblongata, and the dorsal horn of the spinal cord. They can also be found in the periphery, e.g., on autonomic nerves that supply smooth muscles or in inflamed tissue. Opiate receptors are subdivided into μ-, δ-, and χ-receptors. They can be found both presynaptically and postsynaptically. The phosphorylation of presynaptic receptors makes the opening of voltage-dependent presynaptic calcium channels less likely to occur. The resulting depolarization causes a decrease in calcium influx and therefore reduced transmitter release. Many of the central and peripheral effects of opioids can be explained by this process.
Additionally, stimulation of μ-receptors on the postsynaptic membrane of nerve cells can cause improved potassium conductivity. This leads to hyperpolarization and therefore to decreased excitability. The inhibition of the nociceptive afferent conductivity is the foundation of analgesia.
Opioids demonstrate a diverse range of actions and side effects because of their differing affinities for the various opiate receptors. Naloxone is a pure antagonist and is used to antagonize opioids (e.g., to reverse respiratory depression). However, it is important to remember that naloxone has a shorter half-life than most opioids and it may be necessary to administer it several times (continual monitoring is required). Generally speaking, opioids are subdivided into mild (WHO level II) and strong (WHO level III) types, the latter being governed by narcotic laws (Table 4.5).
The opioids are further subdivided into pure agonists that only act on the μ-receptor, agonist–antagonist combinations (pentazocine, tilidine), or partial agonists (buprenorphine). The administration of pure agonists with agonist–antagonists can rapidly become unpredictable and should be avoided. It is hard to maintain a clear overview of the individual substances binding to the receptors, the timing of processes occurring, and the side effects. It is also important to remember that all weak agonists and agonist–antagonists possess a so-called ceiling effect, i.e., above a certain level further dose increases do not result in additional effects. An overview of the most common opioids can be found in Table 4.6.
Tramadol is a weakly acting pure agonist and can be used to supplement highly potent agonists such as morphine when their effect alone is not sufficient. High doses and/or too rapid administration often cause pronounced nausea and vomiting. This unwanted effect can be significantly reduced by the administration of delayed-action drugs. When the theoretical aspects of the effect of tramadol on the uptake of norepinephrine and serotonin are considered, it can be seen that tramadol has a beneficial influence on neuropathic pain. However, combined with other serotonergic substances such as tricyclic antidepressants or monoamine oxidase (MAO) inhibitors, a life-threatening serotonin syndrome is possible.
Pethidine (meperidine) is metabolized into norpethidine, with a half-life up to five times longer, and can result in marked episodes of cramping when it accumulates. Renal failure as well as the induction of hepatic enzymes (e.g., by the use of phenobarbital) increases toxicity.
Although the use of pentazocine (e.g., Fortral) continues to spread, its objective significance in pain therapy is minimal. It acts on the autonomic nervous system, increasing pulse rates and blood pressure in the entire circulatory system, making this drug inappropriate for cardiovascular risk patients.
Valoron N contains the prodrugs tilidine and naloxone, which are enterally resorbed. Tilidine is activated to the clinically effective nortilidine via the first-pass effect in the liver and naloxone is metabolically deactivated. This does not happen when the drug is administered parentally, thus bypassing the first-pass effect, or in the presence of liver failure when metabolization is insufficient.
Buprenorphine is an opioid with a strong analgesic potency. In its transdermal application form,due to its dosages that are available at very low levels, it can already be used for therapy at the transition from level I to level II of the WHO analgesic ladder, and is suitable for the treatment of nonmalignant severe chronic pain such as pain in the context of arthritis or osteoporosis. At the same time, it is approved at higher dosages for transdermal application also for the treatment of severe tumor-related pain. Its side effects are not as burdensome as those of morphine (CNS, constipation, nausea, vomiting) and the development of tolerance also appears to be less frequent. Buprenorphine may even be used in patients with terminal kidney failure. It has a relatively low risk of drug-induced interactions (binding of plasma to globulins instead of albumins).
Morphine is still the classic strong opioid and is currently available for almost every conceivable form of administration. Problems can occur with renal function disorders as a result of the accumulation of the active metabolite morphine-6-glucuronid (M6G), and this can lead to secondary intoxication. In these situations, morphine should be administered with the utmost caution, with reduced dosages and close monitoring.
Changing over to methadone is often wise when patients have developed a tolerance to morphine. Because of the extremely variable half-life, the time required to find the correct dosage is, however, often lengthy and difficult to manage, especially with patients suffering from renal function disorders.
Oxycodone is a semisynthetic morphine derivative with minimal first-pass effect and correspondingly higher bioavailability (60–90%). As it produces no clinically effective active metabolites, oxycodone has an advantage over morphine in the presence of renal function disorders or extremely limited liver function. In addition, patients report fewer central side effects (sedation, fatigue, hallucinations) and constipation. The set combination with naloxone also counteracts the constipation, although only up to the currently approved dosage of 80/40 mg/day. An advantage is that the maximum effect is already reached after 1 hour (vs. 3 hours for delayed-release morphine). However, most likely for this reason, the number of case studies demonstrating the development of psychological dependency (!) is increasing, and this is a point of concern. While oxycodone may play a role in the treatment of acute pain, for chronic pain therapy, at least the indication and dosage must be reexamined on an ongoing basis.
Hydromorphone is the strongest opioid that can be administered orally. It is a semisynthetic dihydromorphine derivative without active metabolites, which also has advantages when renal function is limited. Because of its extremely low plasma protein binding (~8%), it demonstrates less interaction with other medications that are characterized by high levels of protein binding, such as phenprocoumon (Marcoumar), NSAIDs, aspirin, paracetamol, and antidiabetics. Due to the fact that it is largely metabolized independent of the cytochrome P450 system, the use of hydromorphone may be advisable especially in the treatment of elderly and/or multimorbid patients who are dependent on several drugs.
The oral osmotic system (OROS) technology in the drug Jurnista permits a long half-life (the period during which the plasma concentration of the active ingredient is above the half maximal concentration) owing to the ongoing release of the active ingredient, which can reduce the occurrence of end-of-dose pain.
Both mechanisms, MOR and NRI, are synergistically involved in the analgesic effect of tapentadol. The MOR agonism reinforces the body’s own pain-inhibiting opioid mechanism, the NRI component, through the reuptake of norepinephrine, the endogenous monoaminergic, and descending pain modulation. MOR–NRI analgesics can therefore trigger strong pain modulation with relatively low opioid activity and reuptake inhibition. The relatively low involvement of the μ-component in the analgesic effect of tapentadol leads to a low incidence of typical adverse effects associated with opioid and, in turn, leads to significantly better tolerance. Tapentadol is a pure stereoisomer. No metabolites relevant for the analgesic effect of tapentadol exist, which means that it can unleash directly its analgesic effect without metabolic activation. Tapentadol is excreted primarily via the kidneys (99%) and via the feces (1%). Generally, dosage does not have to be adjusted in patients with moderately restricted renal and liver function or elderly patients (>65 years). Tapentadol can be used in adults with severe chronic pain.
The transdermal therapeutic system (TTS) or “patch” offers an alternative noninvasive administration route for strong opioids. In terms of the WHO analgesic ladder, the effectiveness of buprenorphine is comparable to that of a level I–II drug and buprenorphine is comparable with a level II–III drug. Fentanyl is the most effective TTS. By definition, all of the aforementioned TTS are level III drugs and are therefore subject to the provisions of the German narcotics act. The TTS enables a controlled, consistent release of active substances with continual absorption via the skin. It is well accepted by patients and physicians alike, as medication no longer needs to be taken several times a day. It is especially advantageous for forgetful or unreliable patients, and is also convenient for patients who have difficulty swallowing or suffer from other gastrointestinal symptoms. It is, however, a slow-acting system in terms of the uptake of active ingredients. During the first 12 hours, a corresponding oral medication consisting, when possible, of the same active ingredient should be additionally prescribed. When pain additionally peaks, e.g., when weight-bearing, the use of an appropriate rescue medication is also necessary. As a general rule, the patch is changed every 3 days, although experience shows that some patients have to change the patch after 2 to 2.5 days. The Transtec PRO patch releases the active substances evenly up to 96 hours and therefore only has to be changed every 4 days or twice weekly, i.e., every 3.5 days, while Norspan has to be changed every 7 days. In the analgesic dosage range, a ceiling effect of buprenorphine for analgesic is not likely. Furthermore, compared to other strong opioids, buprenorphine has the lowest risk of respiratory depression.
The long-term opioid treatment of chronic musculoskeletal pain is not without controversy, for two reasons: first, this type of pain reacts badly or not at all to the administration of opioids; and second, these drugs have a considerable range of side effects. Whether the use of opioids is really justified in particular cases should therefore be carefully assessed. In addition, the suspension of opioid treatment should be attempted at specific regular intervals. If long-term opioid treatment is decided upon, a slow-release drug should be used for the basic requirements. The dose interval should be guided by the half-life of the medication (Fig. 4.26).
A quick-acting medication with, when possible, the same active ingredients can additionally be prescribed for breakthrough pain. When the effectiveness of the opioid progressively decreases, first of all the opioid sensitivity should be questioned and the dosage should be raised. If the medication continues to be ineffective, or when the side effects become intolerable, a change to another opioid or an alternative administration route should be considered. The equianalgesic dose is used for guidance (see “Effective strength compared to morphine,” Table 4.6), and it is recommended that the initial dosage be reduced by at least a third. At the same time, concomitant psychological conditions must also be considered, with the corresponding psychotherapy interventions.
Geriatric patients cannot always be identified simply by their age in calendar years. Biological age, multiple morbidity, and polypharmacy, as well as the threat of intellectual degradation and/or psychosocial deprivation, are much more important. It is important to bear in mind that pharmacokinetic characteristics are altered in older patients. In clinical practice, the initial dose of opioids should be reduced by 30 to 50%, longer dose intervals should be planned, and the treatment results should be closely monitored, if necessary with the help of relatives. Table 4.7 and Table 4.8provide information on the types of opioids that should be used in the presence of liver or renal failure.
The use of prophylactic laxatives (e.g., Movicol, Laxoberal, Bifiteral) is indicated as adjuvant medication. In some cases, a combination of several drugs, to be taken over the entire duration of opioid treatment, may also be indicated. Antiemetics are often only required, if at all, during the initial period when determining the correct dosage. Central symptoms associated with opioid use, such as sedation, confusion, or hallucinations, should likewise be treated specifically rather than prophylactically (Table 4.9).
Adjuvant analgesics are especially indicated in pain syndromes that are known from experience to be only partly responsive to nonopioids and opioids. This includes, e.g., neuropathic pain, where the dose required for traditional analgesics can be significantly reduced by the specific use of adjuvant medication (McQuay and Moore 1997; Nix 1998; Baron 2000).
The use of tricyclic antidepressants is well established in the treatment of chronic pain, particularly for burning or stabbing pain. Examples of further special indications include chronic tension headaches, fibromyalgia, and posttherapeutic or diabetic neuropathies. Tricyclic antidepressants are assumed to act by modulating descending serotonergic and norepinephrinergic pain control systems. The effects of classic tricyclic antidepressants are the best documented, and the main effects can be divided into three types:
Desipramine type: These substances arouse and improve drive. Anxiety is, if anything, increased. There is a risk of suicide in cases of severe depression as the increase in motivation happens more quickly than the improvement in mood.
We do not yet have sufficient experience or studies of the analgesic components of the more recently developed substances such as the selective serotonin reuptake inhibitors (SSRIs). An attempt to use SSRIs can nevertheless be justified when more traditional medications are not tolerated.
A variety of anticonvulsants act as analgesics in the case of lancinating neuropathic pain. The drugs that have succeeded carbamazepine include oxcarbazepine, gabapentin, and pregabalin, which display significantly fewer unwanted effects. Pregabalin is easy to dose, has a higher receptor affinity, and also has an anxiolytic effect. It should be noted, however, that it has a substantial potential for psychological dependency (Table 4.10).
Increased muscle tension is quite often associated with chronic pain syndromes. The long-term use of benzodiazepines results in dependency without benefits. When the symptoms are suitable, physical therapy should always take priority. Treatment with pharmaceutical muscle relaxants should, if used at all, be kept as brief as possible.
Bisphosphonates act selectively on bone metabolic resorption disorders and inhibit osteoclast activity. Their use is therapeutically indicated, for example, in the treatment of osteoporosis and certain bone metastases.
The pain-relieving effect of calcitonin (e.g., Karil, Miacalcin) is partly to do with its effect on bone metabolism, similar to vitamin D. In addition, it acts as a central analgesic in the initial stages of phantom pain and the “complex regional pain syndrome” (also known as Sudeck’s atrophy).
Corticosteroids have antiedemic and anti-inflammatory effects. They generally act via intracellular receptors. After the corticoids have bound to the receptor, the complex diffuses into the cell nucleus, binds to DNA, and modulates gene expression. Given the nature of this mechanism, it is easy to understand that it takes several hours to days before the effect of the drug can be observed.
The side effects of glucocorticoids are based on the drug’s main actions. Cushing’s syndrome occurs when the individually varying Cushing threshold has been exceeded (daily dosage of ≥ 7.5 mg prednisolone). The following side effects also occur:
In the special case of orthopedic pain therapy on the spine, the administration of minimal amounts of steroids in combination with local anesthetics is limited to single-shot therapy in selected cases only.
Local anesthesia forms the foundation for diagnostic and therapeutic regional anesthesia, neural therapy, and analgesia. Local anesthetics act on the nerve endings, peripheral nerves, and spinal nerves by reversibly blocking the further transmission of cell stimulation. They do this mainly by inhibiting the influx of sodium ions, but also by partially blocking potassium and calcium channels.
Local anesthetics are an effective and low-risk addition when used correctly within pain therapy. They can be combined with opioids, nonopioids, and adjuvant analgesics at any time. The blocking of motor function is correlated with the concentration and the lipophilic nature of each drug. Side effects occur with overdoses or accidental intravascular/subarachnoid injection. CNS effects include episodes of cramping, unconsciousness, and respiratory arrest. Within the cardiovascular system, arrhythmias or ventricular blocks, even asystolia, can occur. Furthermore, there is a risk of allergic reactions and the production of methemoglobin (especially with prilocaine; see Chapter 10).
The most important characteristics of the local anesthetics currently in common use are summarized in Table 4.11.