Yeah I have thought of this before. I have some ideas. Kratom is a good starting point. Mitragynine, the major opioid alkaloid in kratom, should be studied more. Analogs of mitragynine and semi-synthetic derivatives could be the future in safer opiate alternatives, with less harm and side effects.
This article here points to fermented kratom being a good source of less harmful and more effective opioids. Apparently fermentation of the kratom converts the mitragynine into 7-hydroxymitragynine and mitragynine pseudoindoxyl, both of which exceed the potency of morphine and mitragynine by 10-25 fold.
As for synthetic mitragynine analogs, there is 7-acetoxy-mitragynine, the O-acetylated prodrug for 7-hydroxymitragynine. Basically, just like how heroin is O,O-diacetylated -morphine. 7-acetoxymitragynine itself is a weaker opioid agonist, but it should be more potent and act as a prodrug for 7-HO-, because it is more fat soluble and therefore penetrates the blood brain barrier more effectively. The paper on its synthesis and pharmacology can be found here.
There's also this one, MGM-16, which is basically 10-fluoro-7-hydroxymitragynine. It is shown to be even more potent by weight than 7-hydroxymitragynine in animal studies, which itself is already 17-30 times more potent than morphine in mice/rat studies. It is based on the structure of 4-methoxy-5-fluorotryptamine. It is interesting to note that the mitragynine family is a class of indoles; they even have the tryptamine backbone. This means that it might be possible to derive synthetic tryptamines with opioid activity. Mitragynine is actually based on the structure of 4-methoxytryptamine, similar to 4-MeO-MiPT in TIHKAL (which, btw, is reported to have strong sedating and intoxicating effects, often compared to GHB and analgesics/pain killers). Perhaps 4-MeO-tryptamines could even be a potential avenue into exploring novel opioids? 4-MeO-DALT or 4-MeO-5-fluoro-DALT might have significant enough analgesic activity without as much of a psychedelic high.
One last novel opioid which I can think of right now is Cebranopaldol, which is a synthetic derivative of mitragynine which has actually been marketed by a pharmaceutical company for clinical trials. As of 2014 it has entered phase 3 trials so it is in late stage of development. It contains an indole structure but it doesn't have a tryptamine backbone. It retains the 5-fluoro-indole structure that MGM-16 has, which I suppose is important for increasing opioid/analgesic potency.
So I think cebranopaldol, MGM-16, and the acetylated form of MGM-16 might be good potential candidates, however the last two would probably be a bitch to synth.