Propofol can irritate nociceptive receptors or free nerve endings in the peripheral veins, causing pain or discomfort. The direct irritation of the intima by propofol can stimulate the production of bradykinin . Bradykinin is a potent inflammatory factor which can cause vasodilation and hyperpermeability of veins, which in turn increases exposure of the free nerve endings to propofol. PIP lasts for the duration of propofol infusion: one previous paper stated that pain during the early stage was due to direct stimulation of propofol in the veins, while the later pain was due to local generation of bradykinin .
Lidocaine is not only commonly used to alleviate PIP, but is also used as a comparator when studying a new drug to relieve PIP [2, 5, 9, 11, 16, 19]. Therefore, we also chose lidocaine as a comparison to study dezocine and chose the doses of lidocaine according to previous studies. In this study we found that only 40 mg lidocaine could significantly reduce the incidence of total PIP and early PIP. It suggested that mode of action is via blocking the peripheral nerve pathway to produce short-acting local anesthesia. Therefore, lidocaine showed no significant effect on late PIP. Moreover, 10 patients experienced moderate PIP and one patient experienced severe PIP, even when pretreated with lidocaine. Our results also showed that the effect of 40 mg lidocaine on early PIP was statistically better than 20 mg lidocaine, therefore we suppose that larger doses of lidocaine will be more effective to reduce PIP and we will do further study with larger doses of lidocaine in the future.
In our previous pilot study, pretreatment with 1 mg dezocine did not significantly reduce PIP. Therefore, we investigated PIP at larger doses of dezocine in the present study. Our results demonstrated that 2 mg and 4 mg dezocine could significantly reduce the incidence of PIP in both early and late periods and there was no significant difference between the effect of 2 mg and 4 mg dezocine in PIP. No patient experienced severe PIP. This finding is similar to a previous study, which also found that 2 mg dezocine could reduce PIP . However, our study differed in that we studied dezocine at two different doses and propofol infusion at two different time periods. It is useful for us to investigate the mechanisms of how dezocine and lidocaine prevent PIP.
Other previous studies reported that other opioids (remifentanil, alfentanil, fentanil, pethidine) could also alleviate PIP [2, 11, 20, 21], but the precise mechanisms of how opioids prevent PIP remain unclear. One previous study  found no evidence that opioid (alfentanil) application with a tourniquet could relieve pain, suggesting that the effects of opioids on prevention of PIP may be via central, but not peripheral, opioid receptors. However, other studies showed that administration of other opioids (remifentanil, alfentanil) without a tourniquet could alleviate PIP [9, 20, 21]. Dezocine injection was performed without a tourniquet in our study, and we assumed that its effect on PIP was more likely to be mediated via central opioid receptors.
As shown in Fig. 3, either 2 mg or 4 mg dezocine could eliminate early PIP significantly more effectively than 20 mg lidocaine. We also found that 2 mg or 4 mg dezocine could alleviate late PIP significantly more effectively than 20 mg or 40 mg lidocaine, respectively. In terms of total PIP, the relieving effect of 4 mg dezocine was better than 20 mg or 40 mg lidocaine, respectively. Our study also showed that the incidence of total PIP was 25.5% in the 4 mg dezocine group, compared to 53.2% in the 40 mg lidocaine group. Although dezocine could not completely eliminate PIP, its effect on prevention of PIP appeared to be better than lidocaine. On the other hand, it is well worth mentioning that not everyone is fit to receive lidocaine for prevention of PIP due to local anesthetic allergy or arrhythmia. In this population, dezocine may be an effective agent in managing PIP.
Other effective non-pharmacological approaches, or combinations of pharmacological approaches, have been recommended to relieve PIP including warming propofol, venous occlusion with a tourniquet, applying microfiltration and changing the lipid composition [3, 12, 17, 23, 24]. However, no method could eliminate PIP completely and most of these methods were not routinely available in clinical practice except venous occlusion with a tourniquet.
There are some potential limitations in our study. First, although our results showed that 2 mg or 4 mg dezocine could reduce the incidence of PIP, it could not completely eliminate PIP. Future studies could investigate larger doses of dezocine; however, we should also consider the side effects of dezocine with increasing dose. We did not collect information about the effects of dezocine on analgesia and its side effects post-operation. Second, there was a significant difference in age among the five groups, although patients were randomly assigned using computer-generated codes. Therefore, ORs were used to compare the incidence of PIP among the different groups and were adjusted while baseline information was not balanced. Third, we just chose 20 mg or 40 mg lidocaine as a comparison, future studies need considering larger doses of lidocaine.