Kumar MUKESH，PANG Qiying，ZHANG Xiaoqing

Department of Anesthesiology，Tongji Hospital，Tongji University School of Medicine，Shanghai 200065，China

Application of opioid analgesics combined with local anesthetics to spinal anesthesia

Kumar MUKESH，PANG Qiying，ZHANG Xiaoqing

Department of Anesthesiology，Tongji Hospital，Tongji University School of Medicine，Shanghai 200065，China

Though intravertebral anesthesia has numerous potential advantages in some surgeries，unfortunately it also has numerous potential disadvantages，such as hypotension due to sympathetic block，toxicity due to drug overdose，nausea，and vomiting.Recent experiments have shown that the combined application of intrathecal opioids and regional anesthetics can produce obvious synergistic effect-extremely low concentrations of regional anesthetics combined with opioids greatly enhance analgesic effect.There are reports of opioid analgesics administered in intravertebral anesthesia can improve nerve block，prolong the duration of sensory and motor nerve block，enhance regional analgesic effect during operation，extend the time of postoperative analgesia，and decrease the dose of regional anesthetics.Thus，in an attempt to avoid unpleasant side-effects associated with intravertebral anesthesia，opioid analgesics are offered to patients as an additive to intravertebral anesthesia.Binding to its receptor，opioids can stimulate the release of endogenous opioid peptides，and also inhibit the sympathetic nerve to reduce the release of norepinephrine.Therefore，it can enhance the threshold of body pain.

Opioid analgesics；Regional anesthetics；Intravertebral anesthesia

1 Introduction

1.1 Regional anesthesia and general anesthesia

The benefits of epidural anesthesia over general anesthesia include reduced stress response to surgery，less intraoperative blood loss，fewer thromboembolic events，fewer postoperative pulmonary complications，earlier returns of gastrointestinal function，earlier ambulation，earlier hospitaldischarge，and less perioperative mortality along with the fact that it is cheaper.Studies have favored spinal or epidural analgesia overgeneralanesthesia in appropriate cases.This is probably explained by the positive physiological effects of the provided afferent blockade with better initial pain relief，a reducedendocrine metabolic response，and sympathetic blockade with less blood loss and increased leg blood flow，all resulting in reduced cardiopulmonary and thromboembolic events.

1.2 Advantages and disadvantage of intraver-tebral anesthesia

The anesthetic is injected into spinal canal or epidural space，spinal nerve root is blocked，and the corresponding area of nerve root is produced.Based on the specific region of injection，intravertebral anesthesia can be divided into subarachnoid anesthesia（also known asspinalanesthesia），epidural block anesthesia，combined spinal epidural anesthesia，and caudal block anesthesia.

Regional anesthetics have a limited range.They temporarily，completely，and reversibly block nerve conduction at certain specific areas/blocks of human body.However，consciousness is not altered under regional block facilitating surgery[1].The basic difference between regional anesthetics and general anesthetics is：Regional anesthetics are combined with some specific parts of the sodium ion channel on nerve membrane，which can reduce nerve membrane potential through sodium ion channel，leading to nerve impulse conduction block and achieve the effect of anesthesia[2].All the while without altering consciousness，this is not the case with general anaesthesia.

Intravertebral anesthesia in some surgical patients has a number of potential advantage：If little or no intraoperative sedation is required，there will be little or none of the“hangover”effect throughout postoperative period；Patients who express fear about losing consciousness or the loss of control associated with a general anesthetic may prefer a regional technique.And some patients have a strong desire to remain awake to view surgery asitisbeing performed.Regional anesthetic techniques，including spinal and epidural anesthesia，have been offered to patients as an alternative to general anesthesia[3]，in efforts to avoid some of the unpleasant side-effects associated with general anesthesia.

However，spinalorepiduralanesthesia has potential disadvantages： hypotension due to sympathetic block，potential toxicity induced by large doses，nausea，and vomiting[4].Ropivacaine used alone for cesarean section，even when the block level is not low，cannot avoid the traction causes of maternal discomfort and anxiety.It is very important to find some way to avoid the side-effect of regional anesthetics under intravertebral anesthesia.

1.3 Opioid analgesics

Opioids are alkaloids extracted from opium（opium poppy）and derivatives of the body interact with central receptors，which alleviate pain and produce a sense of well-being.Large doses can cause stupor，coma，and respiratory depression[5].

Morphine when used as an analgesic has its own inherentproblems.Respiratory depression is a potential drawback，with anaphylaxis being caused by massive histamine release that potentially presents as skin flushing，hypotension，and bronchial spasm[6].

Fentanyl is a synthetic opioid drug and a potent analgesic.The analgesic effect of fentanyl is 80-100times that of morphine.High-dose fentanyl anesthesia causes tachycardia， occasional hypotension，respiratory depression，and the induction of chest wall stiffness.

Sufentanil which is found in the process of looking for ideal opioid drugs is a step forward.The elimination half-life ofsufentanil（149 min） is shorter than fentanyl（219 min）.The distribution capacity of sufentanil is small，compared to the equivalent amount of fentanyl.Fentanyl，when used in patients with cardiac anesthesia，is featured by earlier anesthetic recovery and prolonged extubating time[7].When used in combination，the drug action intensity is at least 5 times as much as that of fentanyl.Alfentanil is a valuable fentanyl derivative in the benzene pyridine group，with short elimination half-life（72-94 min） and shorteracting time. Therefore，this drug has been widely used for a short-time sustainable intravenous infusion.Its side effects include episodic hypotension， cardiac dysfuction，and chest wall stiffness，which may be related to drug injection speed[8].

1.4 Advantages and disadvantages ofopioid analgesics

Opioids are used for treatment of moderate to severe pain.Clinical experience in the treatment of cancer pain has revealed patients to develop a tolerance to opioids.Other drugs at lower doses could achieve desired analgesic effect with less side effects.

The repeated use of opioids can lead to tolerance and high risks of addiction.Opioid addiction symptomsinclude craving，anxiety，bad mood，yawning，sweating，bumps，tears，runny nose，nausea or vomiting，diarrhea，cramps，muscle pain，fever，and insomnia[9].

Opioid analgesics are excellent additives for patients who require either analgesia during the performance of a painfulblock or adjunctive analgesia during an inadequate block.It can be administered by intravenous bolus or by continuous infusion. Recent reports suggest that opioids administered intravertebrally can be added for regional anesthesia，prolong the duration of sensory and motor nerve block，enhance the regional analgesic effect during operation，and extend the time of postoperative analgesia[10].

Side effects of opioids usually include nausea，vomiting，constipation，and lethargy.The most serious side effects can cause respiratory asphyxia and cardiac arrest.Mild headache，dizziness，lethargy，and miosis indicate that side effects is in nervous system.The nerve damage may come from the opioid receptors in the hypothalamus and stimulation of limbic system[11].Genitourinary effects，including urinary sphincter spasm，bladder urine retention，and losses of libido，are a result of direct stimulation of centralnervoussystem receptorsorsympathetic pathway[12].

1.5 Advantages of combining opioids with regional anesthetics

Local anesthetics are agents that reversibly block localsensory nerve impulses.Localanaesthesia doesn’t alter consciousness and the local tissue pain or discomfort quickly disappears.Local anesthetics have wide but limited range of uses.

Experiments have shown that opioids used in the spinal canal can effectively relieve pain in resting state，but cannot meet the required analgesic effects in active state in patients[13].Butwhen intrathecal opioids are used in combination with regional anesthetics they can produce obvious synergistic effect even when extremely low concentrations of regional anesthetics and opioids are used[14].

A combined sufentanil and bupivacaine fractional dose ED 50[in fractions of the single-dose ED 50 values，i.e.sufentanil 0.85μg（0.36）and bupivacaine 2.2 mg（0.09）respectively]is found to be approximately one-third and one-tenth of the single drug fractional dose[15].Mahon et al.found that fentanyl significantly enhanced the analgesic effect of cocaine when used together with reduced side effects. The combined medication is also widely used in obstetric analgesia.Epidural administration combined with subarachnoid administration is also widely used in obstetric labor analgesia and other postoperative analgesia.By this method，small doses of regional anesthetics combined with opioid analgesics can be selected[16].Fentanyl combined with bupivacaine can accelerate the onset time of bupivacaine in epidural space，and reduce the dosage of bupivacaine[17].Zhang et al.added 3.5 mg morphine to regional anesthetics which was used in brachial plexus block，and 3.5 mg morphine injected postoperatively at the ipsilateral muscular sulcus，and found preemptive analgesia with small doses of morphine in brachial plexus block during surgery and the effective block ofthe formation of Naka Min effect.Also，the postoperative analgesic effect was significantly better than when morphine was injected at the ipsilateral intergroove postoperatively[18].

In abdominal and thoracic surgery and orthopedics anesthesia，intrathecal administration of 0.1-0.5 mg of morphine can achieve satisfactory analgesia，and 0.2-0.3 mg can provide satisfactory postoperative analgesia.

The effect of epidural analgesia is affected by many factors，including type of surgery and surgicalsite，type of pain（childbirth or postoperative pain），loading dose，opioid infusion rate，and patient characteristics.The location of epidural catheter is also very important.Bupivacaine（0.1%）combined with fentanyl can produce obviously low limb motor nerve block，but the same drug used in thoracic epiduralspace does not.Thus，notallopioid analgesics and regional anesthetics used in combination can produce synergistic effects[19].

1.6 The mechanism of action of epidural opioids

The application ofpotentepiduralopioids fentanyl and fentanyl lipophilic in the spinal cord，or actions on the body and their analgesic effect is still controversial[20].

1.7 Direct binding of opioid receptors with spinal dorsal horn

Epidural opioids can directly act on the opioid receptors in dorsal horn of spinal cord，inhibiting the release of presynaptic neurotransmitters in spinal cord，afferent stimulation of noxious stimuli without causing motor or sympathetic blockade.But given the high epiduralopioids，lipophilic can berapidly absorbed by epiduralfatand vasculature into systemic circulation.With the long continuous infusion， due to its high lipophilicity， the concentration in systemic circulation is gradually increased，thereby acting on opioid receptors in central nervous system[21].

1.8 Diffusion of cerebrospinal fluid to head

When comparing epidural sufentanil concentration in different parts of body，researchers found the maximum concentration in cerebrospinal fluid in waist area and later in plasma，but its concentration in cerebrospinal fluid was about 44times higher than that in plasma[22].Although there is a concentration gradient in cerebrospinal fluid，the concentration of the drug is higher around injection sites.

Opioid drugs can be directly administered into the cerebrospinal fluid to achieve a higher concentration.Because the medicine in the epidural space can be combined with epidural fat or absorbed into blood through spinal membrane before the medicine can be absorbed into body. The pharmacokinetics of the drug is more complex，and the amount of charge is 10-20 times of the former（sufentanil concentration in other parts of body）[23].In addition，the effect of analgesia after subarachnoid administration is more precise；it lasts a longer duration，especially for the intensive care unit（ICL）in patientswith combined injury and maternal patients.Research showed that sufentanil when used for subarachnoid and epidural analgesia during labor，better analgesic effect of the former was noted，and the analgesic effect also lasted for a longer period of time. The possibility of delayed respiratory depression aftersubarachnoid administration was greater than that of epidural morphine[24].

1.9 Actions on spinal cord opioid receptors

Opioid receptors are widely distributed in nervous system and the distribution is not uniform.In brain，densities of receptors are high in medial thalamus，ventricle，and periaqueductal gray.The integration ofthese structures is importantfor regulation of pain.The density in limbic system and blue spot nucleus are also high.These structures are related to emotional and spiritual activities.Receptors are also found in the miotic tegmentum of midbrain nuclei，and thenucleusofsolitary tract，along pathways that relate to cough reflex，respiratory and sympathetic nerves，on the extension of brain and gastrointestinal activity（nausea and vomiting reflex）on the brainstem area postrema，dorsal vagal nucleus structure of opioid receptors.In the end of beam nuclear area，glial spinal glial area，opioid receptors are distributed in spinal trigeminal，and the structure is an important transmitter of pain impulses into the central station， affecting afferent nociceptive impulses.Opioid receptors also exist in intestinal muscle.

Opioids are mainly absorbed into central opioid receptors through blood brain barrier.Epidural administration of a single and small dose of opioids is mainly based on the spinal cord[25].

Polley et al.combined epidural bupivacaine with intravenous 30 mg/L fentanyl for labor anesthesia.Required labor analgesia was achieved with fentanyl after epidural analgesia using a sequential method with minimum concentration. When used in combination，epiduralfentanylcan significantly reduce the dosage of epidural bupivacaine in labor analgesia.It has been suggested that the main effect of epidural opioids is in spinal cord[26].Single epidural injection does not lead to this phenomenon. Continuous infusion of fentanyl can take effect in spinal cord[27].

Cohen and Capogna found that the effect of sufentanil in epidural analgesia groups is better than that of intravenous sufentanil group.The epidural sufentanil mainly affected receptors in spinal cord[28].

2 Conclusion

To sum up，the combination of opioids with regional anesthetics can significantly enhance the effect of anesthesia，improve postoperative analgesia，and have less adverse reactions，thus the application isofgreatclinicalvalue.Foropioid-dependent patients，itisadvisable to choose nerve block anesthesia and continuous epidural block anesthesia. Opioid drugs can reduce postoperative analgesia after local anesthesia.

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R614.4+2

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2095-378X（2017）01-0048-05

阿片类镇痛药与局麻药联合应用于椎管内麻醉的效果评价

库马尔，庞启颖，张晓庆
同济大学附属同济医院麻醉科，上海 200065

尽管在某些手术中椎管内麻醉具有许多潜在的优势，但是也存在许多潜在的缺点，比如由于交感神经阻滞导致的低血压、剂量过大导致药物毒性、以及引起患者恶心和呕吐等。近期有研究表明，鞘内联合应用阿片类药物和局麻药可以产生明显的协同效应，极低浓度的局麻药联合阿片类药物能大大增强镇痛效果。有报道称，阿片类镇痛药辅助应用于椎管内麻醉可以加强神经阻滞，延长感觉和运动神经阻滞的持续时间，提高术中区域麻醉的镇痛效果，延长术后镇痛时间，降低局部麻醉的剂量。因此，为了避免椎管内麻醉相关的不良反应，阿片类镇痛药常作为一种添加剂应用于椎管内麻醉中。通过结合其受体，阿片类药物可以刺激内源性阿片肽的释放，抑制交感神经以减少去甲肾上腺素的释放，从而提高人体疼痛的阈值，起到麻醉作用。

阿片类止痛药；局麻药；椎管内麻醉

2016-11-28）

Kumar Mukesh（1983—），男，硕士研究生，研究麻醉学的椎管内麻醉

张晓庆，电子信箱：xq_820175@163.com

10.3969/j.issn.2095-378X.2017.01.015